P301 L, an FTDP-17 Mutant, Exhibits Enhanced Glycation in vitro

Article type: Research Article

Authors: Sonawane, Shweta Kishor^{a; b; *} | Chinnathambi, Subashchandrabose^{a; b; *}

Affiliations: [a] Neurobiology Group, Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India | [b] Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India

Correspondence: [*] Correspondence to: Ms. Shweta Kishor Sonawane and Prof. Subashchandrabose Chinnathambi, Neurobiology group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, 411008 Pune, India. Tel.: +91 20 25902232; Fax: +91 20 25902648; E-mails: [email protected] and [email protected].

Abstract: Background:Frontotemporal dementia and parkinsonism-linked to chromosome-17 are a group of diseases with tau mutations leading to primary tauopathies which include progressive supranuclear palsy, corticobasal syndrome, and frontotemporal lobar degeneration. Alzheimer’s disease is a non-primary tauopathy, which displays tau neuropathology of excess tangle formation and accumulation. FTDP-17 mutations are responsible for early onset of AD, which can be attributed to compromised physiological functions due to the mutations. Tau is a microtubule-binding protein that secures the integrity of polymerized microtubules in neuronal cells. It malfunctions owing to various insults and stress conditions-like mutations and post-translational modifications. Objective:In this study, we modified the wild type and tau mutants by methyl glyoxal and thus studied whether glycation can enhance the aggregation of predisposed mutant tau. Methods:Tau glycation was studied by fluorescence assays, SDS-PAGE analysis, conformational evaluation, and transmission electron microscopy. Results:Our study suggests that FTDP-17 mutant P301 L leads to enhanced glycation-induced aggregation as well as advanced glycation end products formation. Glycation forms amorphous aggregates of tau and its mutants without altering its native conformation. Conclusion:The metabolic anomalies and genetic predisposition have found to accelerate tau-mediated neurodegeneration and prove detrimental for the early-onset of Alzheimer’s disease.

Keywords: Advanced glycation end products, Alzheimer’s disease, FTDP-17, tau glycation

DOI: 10.3233/JAD-191348

Journal: Journal of Alzheimer's Disease, vol. 75, no. 1, pp. 61-71, 2020