Brain Insulin-Like Growth Factor and Neurotrophin Resistance in Parkinson's Disease and Dementia with Lewy Bodies: Potential Role of Manganese Neurotoxicity
Affiliations: Departments of Pathology, Clinical Neuroscience, and Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
Correspondence:
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Corresponding author: Dr. Suzanne M. de la Monte, Pierre Galletti Laboratories, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, RI 02903, USA. Tel.: +1 401 444 7364; Fax: +1 401 444 2939; E-mail: [email protected].
Abstract: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) frequently overlap with Alzheimer's disease, which is linked to brain impairments in insulin, insulin-like growth factor (IGF), and neurotrophin signaling. We explored whether similar abnormalities occur in PD or DLB, and examined the role of manganese toxicity in PD/DLB pathogenesis. Quantitative RT-PCR demonstrated reduced expression of insulin, IGF-II, and insulin, IGF-I, and IGF-II receptors (R) in PD and/or DLB frontal white matter and amygdala, and reduced IGF-IR and IGF-IIR mRNA in DLB frontal cortex. IGF-I and IGF-II resistance was present in DLB but not PD frontal cortex, and associated with reduced expression of Hu, nerve growth factor, and Trk neurotrophin receptors, and increased levels of glial fibrillary acidic protein, α-synuclein, dopamine-β-hydroxylase, 4-hydroxy-2-nonenal (HNE), and ubiquitin immunoreactivity. MnCl2 treatment reduced survival, ATP, and insulin, IGF-I and IGF-II receptor expression, and increased α-synuclein, HNE, and ubiquitin immunoreactivity in cultured neurons. The results suggest that: 1) IGF-I, IGF-II, and neurotrophin signaling are more impaired in DLB than PD, corresponding with DLB's more pronounced neurodegeneration, oxidative stress, and α-synuclein accumulation; 2) MnCl2 exposure causes PD/DLB associated abnormalities in central nervous system neurons, and therefore may contribute to their molecular pathogenesis; and 3) molecular abnormalities in PD/DLB overlap with but are distinguishable from Alzheimer's disease.
Keywords: Central nervous system, dementia with Lewy bodies, human, insulin-like growth factor resistance, neurotrophin, Parkinson's disease, receptor-ligand binding
