You are viewing a javascript disabled version of the site. Please enable Javascript for this site to function properly.
Go to headerGo to navigationGo to searchGo to contentsGo to footer
In content section. Select this link to jump to navigation

Do Changes in Synaptic Autophagy Underlie the Cognitive Impairments in Huntington’s Disease?

Abstract

Although Huntington’s disease (HD) is classically considered from the perspective of the motor syndrome, the cognitive changes in HD are prominent and often an early manifestation of disease. As such, investigating the underlying pathophysiology of cognitive changes may give insight into important and early neurodegenerative events. In this review, we first discuss evidence from both HD patients and animal models that cognitive changes correlate with early pathological changes at the synapse, an observation that is similarly made in other neurodegenerative conditions that primarily affect cognition. We then describe how autophagy plays a critical role supporting synaptic maintenance in the healthy brain, and how autophagy dysfunction in HD may thereby lead to impaired synaptic maintenance and thus early manifestations of disease.

INTRODUCTION

Huntington’s disease (HD) is a progressive neu-rodegenerative condition characterized by a triad of motor, cognitive, and psychiatric symptoms [1]. Historically, much of the focus on HD has been on the motor symptoms; not only is disease onset defined by their development, but changes in motor symptoms is often the primary outcome measure in therapeutic trials in both preclinical and clinical studies. Notwithstanding, the cognitive impairment and psychiatric symptoms occur earlier, and are often more functionally limiting than the impairments in movement [1–8]. Thus, by studying the molecular mechanisms leading to cognitive dysfunction, we hypothesize that we may be able to gain insight into the early stages of disease pathogenesis.

In this review, we will first explore how cognitive dysfunction is an early manifestation of HD, and that similarly to other neurodegenerative diseases that primarily affect cognition, such as Alzheimer’s disease, (AD), dementia with Lewy bodies (DLB), and frontotemporal degeneration (FTD), early deficits in synaptic function may underlie these cognitive symptoms [9, 10]. Next, we will review the growing evidence that the lysosome-mediated degradation pathway autophagy plays a central role in synaptic maintenance, and how the disruption in autophagy may be at the root of the early cognitive changes in HD.

COGNITIVE ALTERATIONS IN HD

the mind becomes more or less impaired, in many amounting to insanity ...  The tendency to insanity ...   is marked.(George Huntington, 1872)

From the earliest descriptions of HD, such as the well-known manuscript by George Huntington in 1872, the cognitive manifestations of the disease have been recognized [11]. In the broadest terms, these are often in the realm of executive function, such as processing speed and set shifting, although there is a vast literature devoted to better defining the specific cognitive and psychiatric manifestations of disease (for review see [12, 13]). The greatest formal insights into these changes have been gained through the study of prodromal HD patients, defined as patients identified as carrying the expanded CAG repeat mutation, but who have not yet developed the extrapyramidal motor syndrome that defines clinical HD [2]. A series of large observational studies of this patient population have provided clear evidence that cognitive changes in HD occur early and can precede motor symptoms (Table 1) [14–21].

Table 1

Large cohort studies of HD natural history

StudyYears enrollingPIProdromal vs early clinical HDNumber of participantsInitial reference and website (if available)
PHAROS1998–2013Ira Shoulson with the Huntington Study Groupprodromal1001[133] Https://huntingtonstudygroup.org/
PREDICT HD2002–2014Jane S. Paulsenprodromal1078[22]
Https://predict-hd.lab.uiowa.edu/
REGISTRY2004–2017G. Bernhard Landwehrmeyerboth14000[14]
COHORT2006–2011Ira Shoulson with the Huntington Study Groupboth2200[134]
TRACK2008–2011Sarah Tabriziboth298[135]
HD-YAS2017–2019Sarah Tabriziprodromal131[26]
ENROLL HD2012–presentG. Bernhard Landwehrmeyerbothstill enrolling[18]
(20131 as of December, 2020)Https://enroll-hd.org/

Briefly, neuropsychological testing indicates that prior to being diagnosed with clinical HD, patients demonstrate psychomotor slowing; deficits on tasks requiring sustained attention; and impairments on a range of other executive functions, including set shifting, sequencing, planning, organizing, and cognitive flexibility [15, 17, 22, 23]. There is also data that memory is affected during prodromal HD, but these findings are less clear, as is the subtype of memory that is most affected, such as visual vs. verbal memory or encoding vs. retrieval. These studies also demonstrate that participants with prodromal HD have difficulty recognizing emotions in facial expression and voices, particularly negative emotions such as anger, fear, and disgust, as well as tasks requiring the related concept of “theory of mind,” or the ability to consider the world from another person’s perspective, as reviewed [2, 24]. These neuropsychiatric features likely begin to develop between 10 and 20 years prior to clinical HD: PREDICT-HD suggested that neurocognitive symptoms could develop up to 15 years before clinical HD [25], whereas the recent HD-Young Adult Study, which evaluated carriers of the expanded CAG repeat who were an average of 23.6 years from predicted clinical HD, found no significant differences in performance on their neuropsychiatric battery relative to control participants, although imaging data suggested that this may in part be due to compensation [26]. Performance on tasks measuring cognitive abilities declines near the onset of clinical HD [27].

SYNAPTIC CHANGES IN HD

It is interesting to note that one of the common themes in neurodegenerative conditions affecting cognition is early synaptic pathology [9]. For example, in AD, synapse loss occurs before cell loss and is a better correlate for cognitive changes than cell loss or the accumulation of pathologic aggregates; and the majority of aggregated alpha-synuclein in post-mortem brains of patients with DLB and Parkinson’s disease is found in presynaptic inclusions rather than Lewy bodies in the soma [9]. Indeed, there is a large amount of evidence suggesting that synaptic dysfunction may be an important step in the pathological cascade of HD as well, although as with all autopsy samples, early changes are difficult to discern. Moreover, correlating findings of neuropathological studies and imaging studies in early disease with the clinical phenotype is often challenging, as subjects are described variably as “prodromal,” “presymptomatic,” and “premanifest,” without a consistent description of the specific assessment scales used to define that clinical stage. Nonetheless, participants labeled with one of these descriptors had not yet begun displaying motor symptoms at a level detectable at the time of last clinical evaluation by the assessments used.

Autopsy studies have long reported neuropathological changes in both pre- and postsynaptic sites in HD post-mortem brain tissue [28–34], but data in subjects with prodromal HD or patients with Vonsattel grades 0 or 1 (suggestive that the samples are analyzed prior to gross cell loss) is limited. Predating Vonsattel grading, medium spiny neurons of adult subjects with clinical HD have been shown to demonstrate morphologic changes in dendrites and alterations in the size, shape, and number of dendritic spines relative to controls [28], which was later confirmed to occur in brains ranging from Vonsattel grades 2–5 [29]. Similar changes were also seen in prefrontal cortical pyramidal cells of Vonsattel grades 2–4 brains from adult HD subjects, in which neurons demonstrated changes to dendritic arborization, length, and surface area [30].

Notably, the finding that the HD gene product huntingtin (Htt) aggregates in neuronal intranuclear inclusions and dystrophic neurites on pathology in post-mortem human brain tissue has offered some clarification on when neuronal processes become involved—studies suggest that dystrophic neurites are present in brains of subjects classified as presymptomatic mutant Htt carriers and early HD cases, whereas the appearance of neuronal intranuclear inclusions coincides with motor symptom onset, but may precede cell death [31, 32, 35]. This is consistent with the hypothesis that alterations in axons are an earlier event in pathogenesis. A study that looked directly at HD pathologic samples from participants classified as presymptomatic revealed a decrease in nerve fiber density, and axonal and synaptic markers [33], supporting this hypothesis. In subjects classified as premanifest, decreased density of the astrocytic glutamate transporter GLT-1 has also been reported, suggesting a potential non-neuronal contribution to synaptic dysfunction [36]. These changes as well as a selective decrease in levels of proteins involved in neurotransmitter release have been observed through all subsequent stages of HD (grades 0–4) [34, 36].

Some of the strongest studies suggesting that axonal and synaptic changes are early events in HD are imaging studies, which have demonstrated that many of the early manifestations of HD may be associated with dysfunction in white matter tracts [37, 38]. In patients with early HD, overall cerebral white matter volume is decreased, and that decrease is correlated with impaired performance on cognitive tasks [39]. Studies examining white matter tracts in pre-symptomatic or early HD patients using diffusion tensor imaging demonstrate a decline in tissue integrity, as measured by decreased fractional anisotropy (FA), in multiple cortical regions, the body of the corpus callosum, and the posterior portion of the internal capsule [40, 41]. Rosas et al. found that the change in FA in the body of the corpus callosum correlated with impairments in cognitive function, as measured by the Stroop color word test. A follow up study further corroborated the tract changes in the corpus callosum in pre-manifest and early HD [42]. It is difficult to determine the proximal cause of white matter changes in these studies. Possibilities include synaptic dysfunction leading to a dying back of the axon tracts, deterioration due to cell death, or a primary pathology within the white matter, as might occur as a result of pathological changes within oligodendrocytes. The authors posit that these white matter changes may occur prior to frank neurodegeneration, given that they occur very early in disease, often decades before expected symptom onset; however, the tract changes were not evaluated relative to atrophy in the connected regions, which would have provided further support for that claim. Similar early changes in white matter tracts have been demonstrated in putamen-prefrontal and prefrontal-parietal tracts, but again, these were not evaluated relative to overall atrophy in the connected regions, making it difficult to eliminate the possibility that these findings are secondary to cell loss [43]. In addition, PET imaging studies evaluating radioligand binding to proteins found in striatal synapses such as phosphodiesterase 10A [44] and the D1 and D2 dopamine receptors [45, 46], have shown decreases in patients with HD; however, these studies did not differentiate if this decreased binding was due to focal synapse loss/dysfunction or general cell loss. Another imaging study in HD shed light on the temporal pattern of synapse loss relative to cell death by demonstrating impairments in sensorimotor tracts in participants classified as having pre-manifest HD, and in multiple white matter tracts, including those of the sensorimotor cortex, corpus callosum, prefrontal cortex, and thalamus in early HD [47]. These affected tracts correlated with deficits in behavioral tasks, but atrophy was only identified in the caudate and corpus callosum, not the thalamus, suggesting that the tract changes to this latter region may predate cell death in the thalamus. Addressing this question from a longitudinal perspective, results of TRACK-HD demonstrated a correlation between the degree of white matter atrophy and progression during the phase of disease prior to onset of motor symptoms, whereas an increase in grey-matter atrophy correlated with impending clinical (i.e., motor) onset [16].

Experimental model systems also strongly support the observation that synaptic dysfunction is an early change in HD. As with human disease, mutant Htt forms neuropil aggregates in mice transgenic for mutant Htt, and although mouse models of HD can vary significantly in design, nearly every model demonstrates synaptic pathology and synaptic plasticity deficits prior to outright cell loss or motoric changes [49–62]. This has been extensively reviewed previously [63], but it is important to note that these synaptic changes are found even in those models that aim to recapitulate HD genetically. For example, knock in mouse models of HD demonstrate neuropil aggregates [62], axonal degeneration [60], and electrophysiological changes [50]. The electrophysiological changes are not limited to hippocampal circuits but in transgenic models, extend broadly to cortico-thalamic and cortico-striatal projections [53, 56, 57, 64]. Moreover, biochemically, changes in synaptic protein levels have been noted in animal models of HD [65–69], and are associated with a decrease in dopamine release in the striatum, even after controlling for a decrease in overall dopamine content [70]. Work in these animal models suggests that early changes in synaptic signaling may then lead to cell toxicity [71], although cell death is not a common feature in the mouse models. Broadly, the synaptic changes observed in HD are similar to other neurodegenerative diseases of cognition, in that post-mortem samples from patients with AD and DLB show early synaptic pathology, and animal models of AD and of synucleinopathies demonstrate electrophysiological changes and abnormal synapse morphology in relevant brain regions [9].

Although in broad strokes the early cognitive changes coupled with synaptic alterations make HD similar to AD, DLB and FTD, it is important to note that there are also clear distinctions, especially clinically. For example, AD demonstrates early, prominent changes in information encoding due to pathology within the hippocampal circuit [72]. Similarly, although the term FTD includes a heterogeneous group of disorders, this class of degenerative conditions tends to demonstrate executive or language impairments, which correlate anatomically with the pathology seen in the frontal and temporal lobes [73]. These differences likely reflect discrete regional vulnerabilities of the disease-initiating protein, but once initiated, the resultant pathological cascade may be very similar at the molecular level [74].

SYNAPTIC AUTOPHAGY AND COGNITIVE DECLINE

Although early synaptic dysfunction and cognitive decline may be found across neurodegenerative disorders, including HD, what causes this dysfunction remains unclear. Growing evidence suggests that the lysosome-mediated degradation pathway autophagy contributes to maintenance of the synapse (Fig. 1) and, as such, it may be involved in the pathologic cascade leading to synapse dysfunction in neurodegenerative conditions. Given the importance of autophagy in maintaining protein and organellar homeostasis, this might be unsurprising. The specialized pre- and postsynaptic sites are adapted for constant activity, with a high density of proteins that are regularly undergoing assembly and disassembly processes [75]. Studies indicate that many synaptic proteins have regions that are disordered [76], making them vulnerable to changes in protein homeostasis which can drive their irreversible aggregation, and thereby disrupt function. Moreover, pre- and post-synaptic sites are brimming with mitochondria, which are used broadly for ATP production, regulation of reactive oxidative stress, and calcium buffering. Autophagy is the only degradation pathway in the cell that can handle the breadth of cytosolic cargoes at the synapse, with the ability to transport individual proteins to entire organelles to the lysosome [77]. The flexibility of this pathway is achieved by two key facets of this pathway: the autophagosome, a double membrane structure that forms de novo to capture cargo; and fusion to the lysosome, an organelle that has the capacity to degrade almost every component of the cell [78].

Fig. 1

Simplified schematic of autophagy at the synapse. It has been suggested that pre-synaptically, autophagosome formation is initiated at the synapse by the generation of an isolation membranes that then close to become autophagosomes. These structures then mature as they travel retrogradely up the axon prior to fusing with lysosomes in the cell body [93–100]. The molecular players governing this pathway are still being investigated but may include the proteins Rab-interacting lysosomal protein (RILP) [138] and Endophilin A [94]. Autophagy has been implicated in the processing of various synaptic proteins (see Table 2) and may be involved in the degradation of entire synaptic vesicles [86, 93]. It is unclear how those proteins and organelles are targeted to the autophagosome, but likely requires adaptor proteins such as p62 [106] and Rab26 [93]. The movement of autophagosomes in dendrites has been less thoroughly studied, although autophagy does seem to be playing a role in this compartment as well, as multiple post-synaptic proteins are also implicated as targets of autophagy (see Table 2). (Figure created with BioRender.com).

Simplified schematic of autophagy at the synapse. It has been suggested that pre-synaptically, autophagosome formation is initiated at the synapse by the generation of an isolation membranes that then close to become autophagosomes. These structures then mature as they travel retrogradely up the axon prior to fusing with lysosomes in the cell body [93–100]. The molecular players governing this pathway are still being investigated but may include the proteins Rab-interacting lysosomal protein (RILP) [138] and Endophilin A [94]. Autophagy has been implicated in the processing of various synaptic proteins (see Table 2) and may be involved in the degradation of entire synaptic vesicles [86, 93]. It is unclear how those proteins and organelles are targeted to the autophagosome, but likely requires adaptor proteins such as p62 [106] and Rab26 [93]. The movement of autophagosomes in dendrites has been less thoroughly studied, although autophagy does seem to be playing a role in this compartment as well, as multiple post-synaptic proteins are also implicated as targets of autophagy (see Table 2). (Figure created with BioRender.com).

In model systems, interventions that alter the amount of autophagic activity (both increases and decreases) lead to impairments in learning and memory [79–84], and it is notable that behavioral changes in response to modulation of autophagy are seen primarily in the cognitive realm. For example, modulation of autophagy in the hippocampus may be important for memory formation, and reversing its decline in aging animals can improve age-related memory deficits [79, 85]. In contrast, disruption of autophagy in dopaminergic neurons does little to disrupt motor performance [86], suggesting that either the reliance on synaptic autophagy is neuronal subtype- or circuit-specific, or that the task itself is less reliant on synaptic flexibility. Interestingly, modulating autophagy in cell culture and animals leads to alterations in dendritic spine morphology and synaptic function [79, 86–92], further supporting the hypothesis that the above changes in learning and memory tasks are mediated by dysregulation of synaptic autophagy.

In animal tissue and neuronal cultures, machinery important for autophagosome formation can be found in the synaptic compartment [93, 94] and autophagosomes that form at the axon terminal mature while travelling retrogradely up the axon to the soma [95–100]. A large number of synaptic proteins have been implicated as targets for autophagy (Table 2) [84, 85, 91, 92, 100–109], suggesting that synaptic proteins are locally taken up by autophagosomes. Many of these proteins are components of the synapse that need to be turned over rapidly in order to facilitate synaptic plasticity, such as proteins required for synaptic vesicle exocytosis, dendritic scaffolding proteins, and post-synaptic neurotransmitter receptors (Table 2). Another feature shared by many of the target proteins is that they have regions that are intrinsically disordered [76], and thus they are aggregation prone, especially if the rate of turnover is decreased. As such, even modest impairments in this function of autophagy could lead to cognitive deficits in tasks that rely on synaptic flexibility.

Table 2

Synaptic proteins implicated as targets of autophagy

Presynaptic proteins
Ca2 + /calmodulin-dependent protein kinase II (CamK2) [84]
Synaptic Vesicle Glycoprotein 2B (SV2b) [103]
SYD-1 [107]
SYD-2/liprin [107]
Synaptobrevin [103, 107]
Tropomyosin receptor kinase B (TrkB) [108]
Synaptotagmin [100]
Synaptophysin [109]
Postsynaptic proteins
Activity-Regulated Cytoskeleton-Associated Protein (Arc/Arg3.1) [85]
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor [104]
glutamate receptor 1 (GluR1) subunit of the AMPA receptor [101, 102]
glutamate receptor 2 (GluR2) subunit of the AMPA receptor [102]
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate receptor 2A (NMDAR2A) [84, 92]
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate receptor 2B (NMDAR2B) [84, 92]
Post-synaptic density protein 95 (PSD-95) [85, 91, 92, 136]
γ-aminobutyric acid A (GABAA) receptor [105]
cholinergic receptor, nicotinic/nicotinic acetylcholine receptor (CHRN) [106]
PTEN-induced kinase 1 (PINK1) [91]
SH3 and multiple ankyrin repeat domains 3 (SHANK3) [91]

As further evidence that autophagy plays a specialized role in the healthy synapse, synaptic activity can reciprocally regulate autophagic activity, especially through neuronal electrical activity [90, 94, 101, 105, 107, 110, 111]. Additionally, training on memory-related tasks leads to region-specific increases in markers of autophagic activity, which localize to the brain region necessary for learning of the task [79]. Further, proteins that play a role in synaptic signaling may also regulate autophagy (Table 3) [91, 103, 112–116]. Together, these studies suggest that synaptic signaling fine-tunes autophagic activity as a way to regulate the turnover of proteins in this compartment (Fig. 2).

Table 3

Synaptic proteins implicated in regulation of autophagy

Snapin [112]
RAB26 [93, 137]
Endophilin A [94]
V100 [113]
Synaptobrevin [114]
Bassoon [103, 115]
Synaptojanin [116]
Brain derived neurotrophic growth factor (BDNF) [91]
Fig. 2

The interplay between autophagy and synaptic activity. In the normal cell, autophagy is both modulated by [90, 94, 101, 105, 107, 110, 111] and modulates [79, 86, 89, 91] synaptic activity to fine-tune synaptic function. Theoretically, autophagic activity can therefore be up or down regulated to either increase or decrease the amount of synaptic protein turnover. This would modulate the strength of the synaptic connections, and thus the amount of synaptic activity. Synaptic activity can then, in turn, feed back to affect the degree of autophagic activity.

The interplay between autophagy and synaptic activity. In the normal cell, autophagy is both modulated by [90, 94, 101, 105, 107, 110, 111] and modulates [79, 86, 89, 91] synaptic activity to fine-tune synaptic function. Theoretically, autophagic activity can therefore be up or down regulated to either increase or decrease the amount of synaptic protein turnover. This would modulate the strength of the synaptic connections, and thus the amount of synaptic activity. Synaptic activity can then, in turn, feed back to affect the degree of autophagic activity.

Despite the accumulation of data supporting the importance of synaptic autophagy in synaptic plasticity, there is still much left to be done in the field. For example, the spatial understanding of where autophagy occurs has been gained largely from embryonic neurons isolated in culture, but has not been confirmed in neurons within adult brains. Moreover, many of the synaptic proteins suggested to be potential autophagic cargo were identified using nonspecific interventions that among other effects, affected levels of autophagic activity, or were simply shown to co-localize with markers of autophagic machinery. Similarly, the studies suggesting a reciprocal relationship between autophagic activity and synaptic signaling did not discern between direct and indirect responses. Although altogether the data is still compelling, the field would benefit from studies using less correlative techniques and, especially in the context of neurodegeneration, studies in the adult and aging brain.

DISRUPTION OF SYNAPTIC MAINTENANCE BY mHtt AND THE ROLE OF AUTOPHAGY

The synapse is an active site that is particularly sensitive to protein homeostasis and membrane trafficking events. Consequently, the mutation underlying HD may be disruptive to the synapse in multiple ways. For example, the expansion of the CAG repeat in the HD gene can affect the normal function of the Htt protein, which has been strongly implicating in membrane trafficking. Htt facilitates the transport of vesicles, including synaptic vesicles, through its interaction with dynein [117], or indirectly with dynactin or with kinesin through Htt-associated protein 1 (HAP1) [118–123]. Further, through interactions with Htt-associated protein 40 (HAP40) [124], Htt also participates in the regulation of endosomal trafficking [125]. As such, the presence of the polyglutamine (polyQ) expansion may interfere with the ability of Htt to interact with its partners, thereby disrupting the trafficking of proteins necessary for synaptic maintenance. Moreover, this disruption in membrane trafficking can also impede autophagy [126] by interfering with the retrograde transport of autophagosomes [127, 128]. Consistent with this, elimination of Htt in Drosophila and the mouse CNS has been reported to decrease autophagic activity [129, 130]. In addition to a direct impact on membrane trafficking, the polyQ expansion can drive aggregation of both the Htt protein as well as its mRNA (reviewed in [127]), placing an increased burden on autophagy as a result of Htt accumulation and thereby impairing autophagic efficiency. Htt may also impact autophagy directly, as it interacts with multiple autophagy related genes, suggesting that it may act as a scaffold for autophagic machinery [129, 130]. Finally, mutant Htt can inhibit Rhes, which through its interaction with mTORC1 can regulate autophagy [131]. Taken together, these data support a model by which mutant Htt leads to decrease in autophagic efficiency, leading to reduced turnover of synaptic proteins and thus cognitive impairment (Fig. 3).

Fig. 3

Proposed pathway of mHtt contribution to cognitive dysfunction and cell death through impairments in synaptic autophagy. mHtt interferes with autophagic efficiency [128–131], leading to a decline in synaptic autophagy. This may in turn interfere with synaptic plasticity, causing both cognitive dysfunction and loss of normal synaptic input to post-synaptic cells and feedback to presynaptic cells. Loss of normal synaptic feedback and input may then contribute to cell death.

Proposed pathway of mHtt contribution to cognitive dysfunction and cell death through impairments in synaptic autophagy. mHtt interferes with autophagic efficiency [128–131], leading to a decline in synaptic autophagy. This may in turn interfere with synaptic plasticity, causing both cognitive dysfunction and loss of normal synaptic input to post-synaptic cells and feedback to presynaptic cells. Loss of normal synaptic feedback and input may then contribute to cell death.

CONCLUSIONS

In summary, there is pathologic and imaging data in individuals with mutations in Htt, as well as evidence from animal models with HD, that suggests that synapse dysfunction may occur early in HD, prior to cell death. Autophagy plays a specialized role in the maintenance and function of the synapse, and mHtt may disrupt this function, leading to the early synaptic changes seen in HD patients and model systems. These synaptic changes may then manifest as impairments in synaptic plasticity and thus cognitive changes early in the disease course. Given that neurons rely on synaptic input and feedback for cell health [132], it is possible that this disruption in synaptic signaling in and of itself contributes to cell death in HD (Fig. 3). There is much work yet to be done in this field –although various groups have demonstrated individual components of this pathway, a direct causal relationship of mutant Htt leading to synaptic dysfunction and, in turn, cognitive impairments, has not yet been demonstrated. However, if the model described herein is born out, targeted interventions to improve the efficiency of synaptic autophagy early in the course of HD could be protective against early cognitive changes and potentially degeneration itself.

REFERENCES

[1] 

Erkkinen MG , Kim M-O , Geschwind MD . Clinical neurology and epidemiology of the major neurodegenerative diseases. Cold Spring Harb Perspect Biol. 2018;10(4):a033118.

[2] 

Paulsen JS , Miller AC , Hayes T , Shaw E . Cognitive and behavioral changes in Huntington disease before diagnosis. Handb Clin Neurol. 2017;144:69–91.

[3] 

Paulsen JS , Ready RE , Hamilton JM , Mega MS , Cummings JL . Neuropsychiatric aspects of Huntington’s disease. J Neurol Neurosurg Psychiatry. 2001;71(3):310–4.

[4] 

Sellers J , Ridner SH , Claassen DO . A systematic review of neuropsychiatric symptoms and functional capacity in Huntington’s disease. J Neuropsychiatry Clin Neurosci. 2020;32(2):109–24.

[5] 

Munhoz RP , Moro A , Silveira-Moriyama L , Teive HA . Non-motor signs in Parkinson’s disease: A review. Arq Neuropsiquiatr. 2015;73(5):454–62.

[6] 

Pigott K , Rick J , Xie SX , Hurtig H , Chen-Plotkin A , Duda JE , Morley JF , Chahine LM , Dahodwala N , Akhtar RS , Siderowf A , Trojanowski JQ , Weintraub D . Longitudinal study of normal cognition in Parkinson disease. Neurology. 2015;85(15):1276–82.

[7] 

Weintraub D , Mamikonyan E . The neuropsychiatry of Parkinson disease: A perfect storm. Am J Geriatr Psychiatry. 2019;27(9):998–1018.

[8] 

Strong MJ , Abrahams S , Goldstein LH , Woolley S , McLaughlin P , Snowden J , Mioshi E , Roberts-South A , Benatar M , Hortobágyi T , Rosenfeld J , Silani V , Ince PG , Turner MR . Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(3-4):153–74.

[9] 

Henstridge CM , Pickett E , Spires-Jones TL . Synaptic pathology: A shared mechanism in neurological disease. Ageing Res Rev. 2016;28:72–84.

[10] 

Clare R , King VG , Wirenfeldt M , Vinters HV . Synapse loss in dementias. J Neurosci Res. 2010;88(10):2083–90.

[11] 

Huntington G . On chorea. Med Surg Reporter. . 1872;26(15):317–21.

[12] 

Paulsen JS . Cognitive impairment in Huntington disease: Diagnosis and treatment. Curr Neurol Neurosci Rep. 2011;11(5):474–83.

[13] 

Roos RA . Huntington’s disease: A clinical review. Orphanet J Rare Dis. 2010;5(1):40.

[14] 

Orth M , Handley OJ , Schwenke C , Dunnett SB , Craufurd D , Ho AK , Wild E , Tabrizi S , Landwehrmeyer GB . Observing Huntington’s disease: The European Huntington’s disease network’s registry. J Neurol Neurosurg Psychiatry. 2011;82(12):1409–12.

[15] 

Paulsen JS , Smith MM , Long JD . Cognitive decline in prodromal Huntington disease: Implications for clinical trials. J Neurol Neurosurg Psychiatry. 2013;84(11):1233–9.

[16] 

Tabrizi SJ , Scahill RI , Owen G , Durr A , Leavitt BR , Roos RA , Borowsky B , Landwehrmeyer B , Frost C , Johnson H , Craufurd D , Reilmann R , Stout JC , Langbehn DR . Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: Analysis of 36-month observational data. Lancet Neurol. 2013;12(7):637–49.

[17] 

Biglan KM , Shoulson I , Kieburtz K , Oakes D , Kayson E , Shinaman MA , Zhao H , Romer M , Young A , Hersch S , Penney J , Marder K , Paulsen J , Quaid K , Siemers E , Tanner C , Mallonee W , Suter G , Dubinsky R , Gray C , Nance M , Bundlie S , Radtke D , Kostyk S , Baic C , Caress J , Walker F , Hunt V , O’Neill C , Chouinard S , Factor S , Greenamyre T , Wood-Siverio C , Corey-Bloom J , Song D , Peavy G , Moskowitz C , Wesson M , Samii A , Bird T , Lipe H , Blindauer K , Marshall F , Zimmerman C , Goldstein J , Rosas D , Novak P , Caviness J , Adler C , Duffy A , Wheelock V , Tempkin T , Richman D , Seeberger L , Albin R , Chou KL , Racette B , Perlmutter JS , Perlman S , Bordelon Y , Martin W , Wieler M , Leavitt B , Raymond L , Decolongon J , Clarke L , Jankovic J , Hunter C , Hauser RA , Sanchez-Ramos J , Furtado S , Suchowersky O , Klimek ML , Guttman M , Sethna R , Feigin A , Cox M , Shannon B , Percy A , Dure L , Harrison M , Johnson W , Higgins D , Molho E , Nickerson C , Evans S , Hobson D , Singer C , Galvez-Jimenez N , Shannon K , Comella C , Ross C , Saint-Hilaire MH , Testa C , Rosenblatt A , Hogarth P , Weiner W , Como P , Kumar R , Cotto C , Stout J , Brocht A , Watts A , Eberly S , Weaver C , Foroud T , Gusella J , Macdonald M , Myers R , Fahn S , Shults C . Clinical-genetic associations in the prospective Huntington at risk observational study (PHAROS). JAMA Neurol. 2016;73(1):102.

[18] 

Landwehrmeyer GB , Fitzer-Attas CJ , Giuliano JD , Gonçalves N , Anderson KE , Cardoso F , Ferreira JJ , Mestre TA , Stout JC , Sampaio C . Data analytics from Enroll-HD, a global clinical research platform for Huntington’s disease. Mov Disord Clin Pract. 2017;4(2):212–24.

[19] 

Shoulson I , Eberly S , Oakes D , Kayson E , Young AB . Phenotype-genotype discrepancies in the prospective Huntington at-risk observational study. Ann Clin Transl Neurol. 2019;6(6):1046–52.

[20] 

Connors MH , Teixeira-Pinto A , Loy CT . Psychosis and longitudinal outcomes in Huntington disease: The COHORT study. J Neurol Neurosurg Psychiatry. 2020;91(1):15–20.

[21] 

Glidden AM , Luebbe EA , Elson MJ , Goldenthal SB , Snyder CW , Zizzi CE , Dorsey ER , Heatwole CR . Patient-reported impact of symptoms in Huntington disease. Neurology. 2020;94(19):e2045–e53.

[22] 

Paulsen JS , Hayden M , Stout JC , Langbehn DR , Aylward E , Ross CA , Guttman M , Nance M , Kieburtz K , Oakes D , Shoulson I , Kayson E , Johnson S , Penziner E , Predict-HD Investigators of the Huntington Study Group. Preparing for preventive clinical trials. Arch Neurol. 2006;63(6):883.

[23] 

Stout JC , Paulsen JS , Queller S , Solomon AC , Whitlock KB , Campbell JC , Carlozzi N , Duff K , Beglinger LJ , Langbehn DR , Johnson SA , Biglan KM , Aylward EH . Neurocognitive signs in prodromal Huntington disease. Neuropsychology. 2011;25(1):1–14.

[24] 

Snowden JS . The neuropsychology of Huntington’s disease. Arch Clin Neuropsychol. 2017;32(7):876–87.

[25] 

Paulsen JS , Langbehn DR , Stout JC , Aylward E , Ross CA , Nance M , Guttman M , Johnson S , Macdonald M , Beglinger LJ , Duff K , Kayson E , Biglan K , Shoulson I , Oakes D , Hayden M . Detection of Huntington’s disease decades before diagnosis: The Predict-HD study. J Neurol Neurosurg Psychiatry. 2008;79(8):874–80.

[26] 

Scahill RI , Zeun P , Osborne-Crowley K , Johnson EB , Gregory S , Parker C , Lowe J , Nair A , O’Callaghan C , Langley C , Papoutsi M , McColgan P , Estevez-Fraga C , Fayer K , Wellington H , Rodrigues FB , Byrne LM , Heselgrave A , Hyare H , Sampaio C , Zetterberg H , Zhang H , Wild EJ , Rees G , Robbins TW , Sahakian BJ , Langbehn D , Tabrizi SJ . Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington’s disease Young Adult Study (HD-YAS): A cross-sectional analysis. Lancet Neurol. 2020;19(6):502–12.

[27] 

Tabrizi SJ , Scahill RI , Durr A , Roos RA , Leavitt BR , Jones R , Landwehrmeyer GB , Fox NC , Johnson H , Hicks SL , Kennard C , Craufurd D , Frost C , Langbehn DR , Reilmann R , Stout JC . Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: The 12-month longitudinal analysis. Lancet Neurol. 2011;10(1):31–42.

[28] 

Graveland G , Williams R , Difiglia M . Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington’s disease. Science. 1985;227(4688):770–3.

[29] 

Ferrante R , Kowall N , Richardson E . Proliferative and degenerative changes in striatal spiny neurons in Huntington’s disease: A combined study using the section-Golgi method and calbindin D28k immunocytochemistry. J Neurosci. 1991;11(12):3877–87.

[30] 

Sotrel A , Williams RS , Kaufmann WE , Myers RH . Evidence for neuronal degeneration and dendritic plasticity in cortical pyramidal neurons of Huntington’s disease: A quantitative Golgi study. Neurology.. 1993;43(10):2088–96.

[31] 

Sapp E , Penney J , Young A , Aronin N , Vonsattel J-P , Difiglia M . Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease. J Neuropathol Exp Neurol. 1999;58(2):165–73.

[32] 

Difiglia M , Sapp E , Chase KO , Davies SW , Bates GP , Vonsattel JP , Aronin N . Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997;277(5334):1990–3.

[33] 

Diprospero NA , Chen E-Y , Charles V , Plomann M , Kordower JH , Tagle DA . Early changes in Huntington’s disease patient brains involve alterations in cytoskeletal and synaptic elements. J Neurocytol. 2004;33(5):517–33.

[34] 

Morton AJ , Faull RLM , Edwardson JM . Abnormalities in the synaptic vesicle fusion machinery in Huntington’s disease. Brain Res Bull. 2001;56(2):111–7.

[35] 

Gutekunst C-A , Li S-H , Yi H , Mulroy JS , Kuemmerle S , Jones R , Rye D , Ferrante RJ , Hersch SM , Li X-J . Nuclear and neuropil aggregates in Huntington’s disease: Relationship to neuropathology. J Neurosci. 1999;19(7):2522–34.

[36] 

Faideau M , Kim J , Cormier K , Gilmore R , Welch M , Auregan G , Dufour N , Guillermier M , Brouillet E , Hantraye P , Deglon N , Ferrante RJ , Bonvento G . In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: A correlation with Huntington’s disease subjects. Hum Mol Genet. 2010;19(15):3053–67.

[37] 

Montoya A , Price BH , Menear M , Lepage M . Brain imaging and cognitive dysfunctions in Huntington’s disease. J Psychiatry Neurosci. 2006;31(1):21–9.

[38] 

Giralt A , Saavedra A , Alberch J , Pérez-Navarro E . Cognitive dysfunction in Huntington’s disease: Humans, mouse models and molecular mechanisms. J Huntingtons Dis. 2012;1(2):155–73.

[39] 

Beglinger LJ , Nopoulos PC , Jorge RE , Langbehn DR , Mikos AE , Moser DJ , Duff K , Robinson RG , Paulsen JS . White matter volume and cognitive dysfunction in early Huntington’s disease. Cogn Behav Neurol.. 2005;18(2):102–7.

[40] 

Reading SAJ , Yassa MA , Bakker A , Dziorny AC , Gourley LM , Yallapragada V , Rosenblatt A , Margolis RL , Aylward EH , Brandt J , Mori S , Van Zijl P , Bassett SS , Ross CA . Regional white matter change in pre-symptomatic Huntington’s disease: A diffusion tensor imaging study. Psychiatry Res Neuroimaging. 2005;140(1):55–62.

[41] 

Rosas HD , Tuch DS , Hevelone ND , Zaleta AK , Vangel M , Hersch SM , Salat DH . Diffusion tensor imaging in presymptomatic and early Huntington’s disease: Selective white matter pathology and its relationship to clinical measures. Mov Disord. 2006;21(9):1317–25.

[42] 

Rosas HD , Lee SY , Bender AC , Zaleta AK , Vangel M , Yu P , Fischl B , Pappu V , Onorato C , Cha J-H , Salat DH , Hersch SM . Altered white matter microstructure in the corpus callosum in Huntington’s disease: Implications for cortical “disconnection”. Neuroimage. 2010;49(4):2995–3004.

[43] 

Poudel GR , Stout JC , Domínguez D JF , Salmon L , Churchyard A , Chua P , Georgiou-Karistianis N , Egan GF . White matter connectivity reflects clinical and cognitive status in Huntington’s disease. Neurobiol Dis. 2014;65:180–7.

[44] 

Ahmad R , Bourgeois S , Postnov A , Schmidt ME , Bormans G , Van Laere K , Vandenberghe W . PET imaging shows loss of striatal PDE10A in patients with Huntington disease. Neurology. 2014;82(3):279–81.

[45] 

Turjanski N , Weeks R , Dolan R , Harding AE , Brooks DJ . Striatal D1 and D2 receptor binding in patients with Huntington’s disease and other choreas a PET study. Brain. 1995;118(3):689–96.

[46] 

Pavese N , Andrews TC , Brooks DJ , Ho AK , Rosser AE , Barker RA , Robbins TW , Sahakian BJ , Dunnett SB , Piccini P . Progressive striatal and cortical dopamine receptor dysfunction in Huntington’s disease: A PET study. Brain. 2003;126(5):1127–35.

[47] 

Dumas EM , Van Den Bogaard SJA , Ruber ME , Reilmann R , Stout JC , Craufurd D , Hicks SL , Kennard C , Tabrizi SJ , Van Buchem MA , Van Der Grond J , Roos RAC . Early changes in white matter pathways of the sensorimotor cortex in premanifest Huntington’s disease. Hum Brain Mapp. 2012;33(1):203–12.

[48] 

Li H , Li S-H , Cheng AL , Mangiarini L , Bates GP , Li X-J . Ultrastructural localization and progressive formation of neuropil aggregates in Huntington’s disease transgenic mice. Hum Mol Genet. 1999;8(7):1227–36.

[49] 

Quirion JG , Parsons MP . The onset and progression of hippocampal synaptic plasticity deficits in the Q175FDN mouse model of Huntington disease. Front Cell Neurosci. 2019;13.

[50] 

Usdin MT , Shelbourne PF , Myers RM , Madison DV . Impaired synaptic plasticity in mice carrying the Huntington’s disease mutation. Hum Mol Genet. 1999;8(5):839–46.

[51] 

Murphy KP , Carter RJ , Lione LA , Mangiarini L , Mahal A , Bates GP , Dunnett SB , Morton AJ . Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington’s disease mutation. J Neurosci. 2000;20(13):5115–23.

[52] 

Lynch G , Kramar EA , Rex CS , Jia Y , Chappas D , Gall CM , Simmons DA . Brain-derived neurotrophic factor restores synaptic plasticity in a knock-in mouse model of Huntington’s disease. J Neurosci. 2007;27(16):4424–34.

[53] 

Kolodziejczyk K , Parsons MP , Southwell AL , Hayden MR , Raymond LA . Striatal synaptic dysfunction and hippocampal plasticity deficits in the Hu97/18 mouse model of Huntington disease. PLoS One. 2014;9(4):e94562.

[54] 

Cummings DM , Milnerwood AJ , Dallérac GM , Vatsavayai SC , Hirst MC , Murphy KPSJ . Abnormal cortical synaptic plasticity in a mouse model of Huntington’s disease. Brain Res Bull. 2007;72(2-3):103–7.

[55] 

Cummings DM , Milnerwood AJ , Dallérac GM , Waights V , Brown JY , Vatsavayai SC , Hirst MC , Murphy KPSJ . Aberrant cortical synaptic plasticity and dopaminergic dysfunction in a mouse model of Huntington’s disease. Hum Mol Genet. 2006;15(19):2856–68.

[56] 

Klapstein GJ , Fisher RS , Zanjani H , Cepeda C , Jokel ES , Chesselet MF , Levine MS . Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington’s disease transgenic mice. J Neurophysiol. 2001;86(6):2667–77.

[57] 

Cepeda C , Hurst RS , Calvert CR , Hernández-Echeagaray E , Nguyen OK , Jocoy E , Christian LJ , Ariano MA , Levine MS . Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington’s disease. J Neurosci. 2003;23(3):961–9.

[58] 

Spires TL , Grote HE , Garry S , Cordery PM , Van Dellen A , Blakemore C , Hannan AJ . Dendritic spine pathology and deficits in experience-dependent dendritic plasticity in R6/1 Huntington’s disease transgenic mice. Eur J Neurosci. 2004;19(10):2799–807.

[59] 

Guidetti P , Charles V , Chen E-Y , Reddy PH , Kordower JH , Whetsell WO , Schwarcz R , Tagle DA . Early degenerative changes in transgenic mice expressing mutant huntingtin involve dendritic abnormalities but no impairment of mitochondrial energy production. Exp Neurol. 2001;169(2):340–50.

[60] 

Li H , Li S-H , Yu Z-X , Shelbourne P , Li X-J . Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington’s disease mice. J Neurosci. 2001;21(21):8473–81.

[61] 

Wegrzynowicz M , Bichell TJ , Soares BD , Loth MK , McGlothan JS , Mori S , Alikhan FS , Hua K , Coughlin JM , Holt HK , Jetter CS , Pomper MG , Osmand AP , Guilarte TR , Bowman AB . Novel BAC mouse model of Huntington’s disease with 225 CAG repeats exhibits an early widespread and stable degenerative phenotype. J Huntingtons Dis. 2015;4(1):17–36.

[62] 

Menalled LB , Sison JD , Dragatsis I , Zeitlin S , Chesselet M-F . Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington’s disease with 140 CAG repeats. J Comp Neurol. . 2003;465(1):11–26.

[63] 

Li J-Y , Conforti L . Axonopathy in Huntington’s disease. Exp Neurol. 2013;246:62–71.

[64] 

Milnerwood AJ , Gladding CM , Pouladi MA , Kaufman AM , Hines RM , Boyd JD , Ko RW , Vasuta OC , Graham RK , Hayden MR , Murphy TH , Raymond LA . Early increase in extrasynaptic nmda receptor signaling and expression contributes to phenotype onset in Huntington’s disease mice. Neuron. 2010;65(2):178–90.

[65] 

Morton AJ , Edwardson JM . Progressive depletion of complexin II in a transgenic mouse model of Huntington’s disease. J Neurochem. 2001;76(1):166–72.

[66] 

Peng C , Zhu G , Liu X , Li H . Mutant huntingtin causes a selective decrease in the expression of synaptic vesicle protein 2C. Neurosci Bull. 2018;34(5):747–58.

[67] 

Smith R , Petersén Å , Bates GP , Brundin P , Li J-Y . Depletion of rabphilin 3A in a transgenic mouse model (R6/1) of Huntington’s disease, a possible culprit in synaptic dysfunction. Neurobiol Dis. 2005;20(3):673–84.

[68] 

Freeman W , Morton AJ . Regional and progressive changes in brain expression of complexin II in a mouse transgenic for the Huntington’s disease mutation. Brain Res Bull. 2004;63(1):45–55.

[69] 

Sapp E , Seeley C , Iuliano M , Weisman E , Vodicka P , Difiglia M , Kegel-Gleason KB . Protein changes in synaptosomes of Huntington’s disease knock-in mice are dependent on age and brain region. Neurobiol Dis. 2020;141:104950.

[70] 

Callahan JW , Abercrombie ED . In vivo dopamine efflux is decreased in striatum of both fragment (R6/2) and full-length (YAC128) transgenic mouse models of Huntington’s disease. Front Syst Neurosci. 2011;5.

[71] 

Plotkin JL , Surmeier DJ . Corticostriatal synaptic adaptations in Huntington’s disease. Curr Opin Neurobiol. 2015;33:53–62.

[72] 

Khan QuA , Graff-Radford NR . Alzheimer’s disease. In: Schapira A, Wszolek Z, Dawson TM, Wood N, editors. Neurodegeneration. Hoboken, NJ: John Wiley & Sons, Ltd; 2017. pp. 102-14.

[73] 

Wider CW , Jasinska-Myga B , Konno T , Wszolek ZK . Frontotemporal dementia. In: Schapira A, Wszolek Z, Dawson TM, Wood N, editors. Neurodegeneration. Hoboken, NJ: John Wiley & Sons, Ltd; 2017. pp. 115-25.

[74] 

Wolfe MS . Chapter 1 - solving the puzzle of neurodegeneration. In: Wolfe MS, editor. The molecular and cellular basis of neurodegenerative diseases: Academic Press; 2018. pp. 1-22.

[75] 

Vijayan V , Verstreken P . Autophagy in the presynaptic compartment in health and disease. J Cell Biol. 2017;216(7):1895–906.

[76] 

Snead D , Eliezer D . Intrinsically disordered proteins in synaptic vesicle trafficking and release. J Biol Chem. 2019;294(10):3325–42.

[77] 

Yamamoto A , Yue Z . Autophagy and its normal and pathogenic states in the brain. Annu Rev Neurosci. 2014;37:55–78.

[78] 

Fox LM , Yamamoto A . Macroautophagy of aggregation-prone proteins in neurodegenerative disease. In: Hayat MA, editor. Autophagy: Cancer, other pathologies, inflammation, immunity, infection, and aging: Elsevier; 2015. pp. 117-137.

[79] 

Glatigny M , Moriceau S , Rivagorda M , Ramos-Brossier M , Nascimbeni AC , Lante F , Shanley MR , Boudarene N , Rousseaud A , Friedman AK , Settembre C , Kuperwasser N , Friedlander G , Buisson A , Morel E , Codogno P , Oury F . Autophagy is required for memory formation and reverses age-related memory decline. Curr Biol. 2019;29(3):435–48 e8.

[80] 

Zhao YG , Sun L , Miao G , Ji C , Zhao H , Sun H , Miao L , Yoshii SR , Mizushima N , Wang X , Zhang H . The autophagy gene Wdr45/Wipi4 regulates learning and memory function and axonal homeostasis. Autophagy. 2015;11(6):881–90.

[81] 

Li P , Hao XC , Luo J , Lv F , Wei K , Min S . Propofol mitigates learning and memory impairment after electroconvulsive shock in depressed rats by inhibiting autophagy in the hippocampus. Med Sci Monit. 2016;22:1702–8.

[82] 

Li Z , Hao S , Yin H , Gao J , Yang Z . Autophagy ameliorates cognitive impairment through activation of PVT1 and apoptosis in diabetes mice. Behav Brain Res. 2016;305:265–77.

[83] 

Hylin MJ , Zhao J , Tangavelou K , Rozas NS , Hood KN , MacGowan JS , Moore AN , Dash PK . A role for autophagy in long-term spatial memory formation in male rodents. J Neurosci Res. 2018;96(3):416–26.

[84] 

Zhai B , Shang X , Fu J , Li F , Zhang T . Rapamycin relieves anxious emotion and synaptic plasticity deficits induced by hindlimb unloading in mice. Neurosci Lett. 2018;677:44–8.

[85] 

Yan J , Porch MW , Court-Vazquez B , Bennett MVL , Zukin RS . Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice. Proc Natl Acad Sci U S A. 2018;115(41):E9707–E16.

[86] 

Hernandez D , Torres CA , Setlik W , Cebrian C , Mosharov EV , Tang G , Cheng HC , Kholodilov N , Yarygina O , Burke RE , Gershon M , Sulzer D . Regulation of presynaptic neurotransmission by macroautophagy. Neuron. 2012;74(2):277–84.

[87] 

Tang G , Gudsnuk K , Kuo SH , Cotrina ML , Rosoklija G , Sosunov A , Sonders MS , Kanter E , Castagna C , Yamamoto A , Yue Z , Arancio O , Peterson BS , Champagne F , Dwork AJ , Goldman J , Sulzer D . Loss of mtor-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron. 2014;83(5):1131–43.

[88] 

Xi Y , Dhaliwal JS , Ceizar M , Vaculik M , Kumar KL , Lagace DC . Knockout of atg5 delays the maturation and reduces the survival of adult-generated neurons in the hippocampus. Cell Death Dis. 2016;7:e2127.

[89] 

Fu J , Wang H , Gao J , Yu M , Wang R , Yang Z , Zhang T . Rapamycin effectively impedes melamine-induced impairments of cognition and synaptic plasticity in wistar rats. Mol Neurobiol. 2017;54(2):819–32.

[90] 

Kimura T , Suzuki M , Akagi T . Age-dependent changes in synaptic plasticity enhance tau oligomerization in the mouse hippocampus. Acta Neuropathol Commun. 2017;5(1):67.

[91] 

Nikoletopoulou V , Sidiropoulou K , Kallergi E , Dalezios Y , Tavernarakis N . Modulation of autophagy by BDNF underlies synaptic plasticity. Cell Metab. 2017;26(1):230–42 e5.

[92] 

Zhang H , Shang Y , Xiao X , Yu M , Zhang T . Prenatal stress-induced impairments of cognitive flexibility and bidirectional synaptic plasticity are possibly associated with autophagy in adolescent male-offspring. Exp Neurol. 2017;298(Pt A):68–78.

[93] 

Binotti B , Pavlos NJ , Riedel D , Wenzel D , Vorbruggen G , Schalk AM , Kuhnel K , Boyken J , Erck C , Martens H , Chua JJ , Jahn R . The GTPase Rab26 links synaptic vesicles to the autophagy pathway. Elife. 2015;4:e05597.

[94] 

Soukup SF , Kuenen S , Vanhauwaert R , Manetsberger J , Hernandez-Diaz S , Swerts J , Schoovaerts N , Vilain S , Gounko NV , Vints K , Geens A , De Strooper B , Verstreken P . A LRRK2-dependent EndophilinA phosphoswitch is critical for macroautophagy at presynaptic terminals. Neuron. 2016;92(4):829–44.

[95] 

Hollenbeck PJ . Products of endocytosis and autophagy are retrieved from axons by regulated retrograde organelle transport. J Cell Biol. 1993;121(2):305–15.

[96] 

Lee S , Sato Y , Nixon RA . Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer’s-like axonal dystrophy. J Neurosci. 2011;31(21):7817–30.

[97] 

Maday S , Wallace KE , Holzbaur EL . Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons. J Cell Biol. 2012;196(4):407–17.

[98] 

Maday S , Holzbaur EL . Autophagosome biogenesis in primary neurons follows an ordered and spatially regulated pathway. Dev Cell. 2014;30(1):71–85.

[99] 

Maday S , Holzbaur EL . Compartment-specific regulation of autophagy in primary neurons. J Neurosci. 2016;36(22):5933–45.

[100] 

Jin EJ , Kiral FR , Ozel MN , Burchardt LS , Osterland M , Epstein D , Wolfenberg H , Prohaska S , Hiesinger PR . Live observation of two parallel membrane degradation pathways at axon terminals. Curr Biol. 2018;28(7):1027–38 e4.

[101] 

Shehata M , Matsumura H , Okubo-Suzuki R , Ohkawa N , Inokuchi K . Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression. J Neurosci. 2012;32(30):10413–22.

[102] 

Xu LX , Tang XJ , Yang YY , Li M , Jin MF , Miao P , Ding X , Wang Y , Li YH , Sun B , Feng X . Neuroprotective effects of autophagy inhibition on hippocampal glutamate receptor subunits after hypoxia-ischemia-induced brain damage in newborn rats. Neural Regen Res.. 2017;12(3):417–24.

[103] 

Hoffmann-Conaway S , Brockmann MM , Schneider K , Annamneedi A , Rahman KA , Bruns C , Textoris-Taube K , Trimbuch T , Smalla K-H , Rosenmund C , Gundelfinger ED , Garner CC , Montenegro-Venegas C . Parkin contributes to synaptic vesicle autophagy in Bassoon-deficient mice. eLife. 2020;9:e56590.

[104] 

Matsuda S , Miura E , Matsuda K , Kakegawa W , Kohda K , Watanabe M , Yuzaki M . Accumulation of AMPA receptors in autophagosomes in neuronal axons lacking adaptor protein AP-4. Neuron. 2008;57(5):730–45.

[105] 

Rowland AM , Richmond JE , Olsen JG , Hall DH , Bamber BA . Presynaptic terminals independently regulate synaptic clustering and autophagy of GABAA receptors in Caenorhabditis elegans. J Neurosci. 2006;26(6):1711–20.

[106] 

Khan MM , Strack S , Wild F , Hanashima A , Gasch A , Brohm K , Reischl M , Carnio S , Labeit D , Sandri M , Labeit S , Rudolf R . Role of autophagy, SQSTM1, SH3GLB1, and TRIM63 in the turnover of nicotinic acetylcholine receptors. Autophagy. 2014;10(1):123–36.

[107] 

Hill SE , Kauffman KJ , Krout M , Richmond JE , Melia TJ , Colón-Ramos DA . Maturation and clearance of autophagosomes in neurons depends on a specific cysteine protease isoform, ATG-4.2. Dev Cell. 2019;49(2):251–66.e8.

[108] 

Kononenko NL , Classen GA , Kuijpers M , Puchkov D , Maritzen T , Tempes A , Malik AR , Skalecka A , Bera S , Jaworski J , Haucke V . Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration. Nat Commun. 2017;8:14819.

[109] 

Hoffmann S , Orlando M , Andrzejak E , Bruns C , Trimbuch T , Rosenmund C , Garner CC , Ackermann F . Light-activated ROS production induces synaptic autophagy. J Neurosci. 2019;39(12):2163–83.

[110] 

Wang T , Martin S , Papadopulos A , Harper CB , Mavlyutov TA , Niranjan D , Glass NR , Cooper-White JJ , Sibarita JB , Choquet D , Davletov B , Meunier FA . Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type a. J Neurosci. 2015;35(15):6179–94.

[111] 

Wang T , Martin S , Nguyen TH , Harper CB , Gormal RS , Martinez-Marmol R , Karunanithi S , Coulson EJ , Glass NR , Cooper-White JJ , van Swinderen B , Meunier FA . Flux of signalling endosomes undergoing axonal retrograde transport is encoded by presynaptic activity and TrkB. Nat Commun. 2016;7:12976.

[112] 

Cai Q , Lu L , Tian JH , Zhu YB , Qiao H , Sheng ZH . Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons. Neuron. 2010;68(1):73–86.

[113] 

Williamson WR , Wang D , Haberman AS , Hiesinger PR . A dual function of V0-ATPase a1 provides an endolysosomal degradation mechanism in Drosophila melanogaster photoreceptors. J Cell Biol. 2010;189(5):885–99.

[114] 

Haberman A , Williamson WR , Epstein D , Wang D , Rina S , Meinertzhagen IA , Hiesinger PR . The synaptic vesicle snare neuronal synaptobrevin promotes endolysosomal degradation and prevents neurodegeneration. J Cell Biol. 2012;196(2):261–76.

[115] 

Okerlund ND , Schneider K , Leal-Ortiz S , Montenegro-Venegas C , Kim SA , Garner LC , Waites CL , Gundelfinger ED , Reimer RJ , Garner CC . Bassoon controls presynaptic autophagy through atg5. Neuron. 2017;93(4):897–913 e7.

[116] 

Vanhauwaert R , Kuenen S , Masius R , Bademosi A , Manetsberger J , Schoovaerts N , Bounti L , Gontcharenko S , Swerts J , Vilain S , Picillo M , Barone P , Munshi ST , de Vrij FM , Kushner SA , Gounko NV , Mandemakers W , Bonifati V , Meunier FA , Soukup SF , Verstreken P . The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals. EMBO J. 2017;36(10):1392–411.

[117] 

Caviston JP , Ross JL , Antony SM , Tokito M , Holzbaur ELF . Huntingtin facilitates dynein/dynactin-mediated vesicle transport. Proc Natl Acad Sci U S A. 2007;104(24):10045–50.

[118] 

Engelender S , Sharp AH , Colomer V , Tokito MK , Lanahan A , Worley P , Holzbaur EL , Ross CA . Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Hum Mol Genet. 1997;6(13):2205–12.

[119] 

Gauthier LR , Charrin BC , Borrell-Pagès M , Dompierre JP , Rangone H , Cordelières FP , De Mey J , Macdonald ME , Lessmann V , Humbert S , Saudou F . Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell. 2004;118(1):127–38.

[120] 

Li S-H , Gutekunst C-A , Hersch SM , Li X-J . Interaction of huntingtin-associated protein with dynactin p150glued . J Neurosci. 1998;18(4):1261–9.

[121] 

McGuire JR , Rong J , Li S-H , Li X-J . Interaction of huntingtin-associated protein-1 with kinesin light chain. J Biol Chem. 2006;281(6):3552–9.

[122] 

Twelvetrees AE , Yuen EY , Arancibia-Carcamo IL , Macaskill AF , Rostaing P , Lumb MJ , Humbert S , Triller A , Saudou F , Yan Z , Kittler JT . Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin. Neuron. 2010;65(1):53–65.

[123] 

Zala D , Hinckelmann M-V , Saudou F . Huntingtin’s function in axonal transport is conserved in Drosophila melanogaster. PLoS One. 2013;8(3):e60162.

[124] 

Guo Q , Bin H , Cheng J , Seefelder M , Engler T , Pfeifer G , Oeckl P , Otto M , Moser F , Maurer M , Pautsch A , Baumeister W , Fernández-Busnadiego R , Kochanek S . The cryo-electron microscopy structure of huntingtin. Nature. 2018;555(7694):117–20.

[125] 

Pal A , Severin F , Lommer B , Shevchenko A , Zerial M . Huntingtin– HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington’s disease. J Cell Biol. 2006;172(4):605–18.

[126] 

Cortes CJ , La Spada AR . The many faces of autophagy dysfunction in Huntington’s disease: From mechanism to therapy. Drug Discov Today. 2014;19(7):963–71.

[127] 

Croce KR , Yamamoto A . A role for autophagy in Huntington’s disease. Neurobiol Dis. 2019;122:16–22.

[128] 

Wong YC , Holzbaur ELF . The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J Neurosci. 2014;34(4):1293–305.

[129] 

Ochaba J , Lukacsovich T , Csikos G , Zheng S , Margulis J , Salazar L , Mao K , Lau AL , Yeung SY , Humbert S , Saudou F , Klionsky DJ , Finkbeiner S , Zeitlin SO , Marsh JL , Housman DE , Thompson LM , Steffan JS . Potential function for the huntingtin protein as a scaffold for selective autophagy. Proc Natl Acad Sci U S A. 2014;111(47):16889–94.

[130] 

Rui Y-N , Xu Z , Patel B , Chen Z , Chen D , Tito A , David G , Sun Y , Stimming EF , Bellen HJ , Cuervo AM , Zhang S . Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol. 2015;17(3):262–75.

[131] 

Mealer RG , Murray AJ , Shahani N , Subramaniam S , Snyder SH . Rhes, a striatal-selective protein implicated in Huntington disease, binds beclin-1 and activates autophagy. J Biol Chem. 2014;289(6):3547–54.

[132] 

Fricker M , Tolkovsky AM , Borutaite V , Coleman M , Brown GC . Neuronal cell death. Physiol Rev. 2018;98(2):813–80.

[133] 

Huntington Study Group PHAROS Investigators. At risk for Huntington disease. Arch Neurol. 2006;63(7):991.

[134] 

Dorsey ER , Huntington Study Group COHORT Investigators. Characterization of a large group of individuals with Huntington disease and their relatives enrolled in the COHORT study. PLoS One. 2012;7(2):e29522.

[135] 

Tabrizi SJ , Langbehn DR , Leavitt BR , Roos RA , Durr A , Craufurd D , Kennard C , Hicks SL , Fox NC , Scahill RI , Borowsky B , Tobin AJ , Rosas HD , Johnson H , Reilmann R , Landwehrmeyer B , Stout JC . Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: Cross-sectional analysis of baseline data. Lancet Neurol. 2009;8(9):791–801.

[136] 

Domise M , Sauve F , Didier S , Caillerez R , Begard S , Carrier S , Colin M , Marinangeli C , Buee L , Vingtdeux V . Neuronal AMP-activated protein kinase hyper-activation induces synaptic loss by an autophagy-mediated process. Cell Death Dis. 2019;10(3):221.

[137] 

Luningschror P , Binotti B , Dombert B , Heimann P , Perez-Lara A , Slotta C , Thau-Habermann N , C RvC , Karl F , Damme M , Horowitz A , Maystadt I , Fuchtbauer A , Fuchtbauer EM , Jablonka S , Blum R , Uceyler N , Petri S , Kaltschmidt B , Jahn R , Kaltschmidt C , Sendtner M . Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease. Nat Commun. 2017;8(1):678.

[138] 

Khobrekar NV , Quintremil S , Dantas TJ , Vallee RB . The dynein adaptor RILP controls neuronal autophagosome biogenesis, transport, and clearance. Dev Cell. 2020;53(2):141–53.e4.