Objective: To elucidate, the molecular mechanism underlying glycated α-Syn mediated dopaminergic (DAergic) neurodegeneration in the substantia nigra (SN) via the AGE/RAGE signaling pathway.

Background: Intracytoplasmic inclusion of Lewy bodies, primarily containing α-Syn, is a pathological hallmark for Parkinson’s disease. While the glycation with methylglyoxal results in α-Syn misfolded and aggregation has been studied, the effects of glycated α-Syn and how it affects the α-Syn aggregation at the early onset of Parkinson’s disease have not been investigated.

Method: Through rDNA technology, we first purified and characterized recombinant human α-Syn (rh α-Syn). We established that glycation (an unavoidable age-associated post-translational modification) with d-ribose and characterized it by LC-MS/MS, transmission electron microscopy (TEM), MALDI TOF-MS and atomic force microscopy (AFM) analysis. Furthermore, post-translational toxicity of α-Syn was investigated in wild-type ICR mice by intranigral injection of a single dosage of glycated α-Syn (2µg/µl). Behavioral assessments were done every week. To check glycated α-Syn induced neurodegeneration, age-dependent sensitivity of DAergic neurons, and contribution in AGE/RAGE signaling cascade, immunohistochemical analysis were performed at different time points (28, and 56-day post-surgery).

Results: After rh α-Syn was successfully purified, we found the mass increment (~2kDa) of glycated α-Syn by using MALDI TOF-MS. This was supported by the use of TEM and AFM to find alterations in the internal structure of this protein. At 56-days post-surgery, immunofluorescence labeling revealed an upregulation of RAGE resulting in significant loss of TH⁺ neurons in substantia nigra pars compacta (SNc). Iba1 and GFAP expression were elevated in order to activate the inflammatory cascade caused by RAGE. Additionally, we found that glycated α-Syn increased malondialdehyde levels resulting in ROS production, which may have contributed to the upregulation of caspases which lead to the age-dependent sensitivity of DAergic neurons to degeneration by activating RAGE.

Conclusion: We uncovered that d-ribose-derived glycation played a significant role in the exacerbation or anticipation of early onset of PD-like symptoms, indicating that anti-glycation or anti-diabetic agents may be effective in treating Parkinson’s disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/glycated-alpha-synuclein-and-it-emerging-role-in-early-onset-of-parkinsons-disease/