Glycated α-Synuclein Renders Glial Cell Activation and Induces Degeneration of Dopaminergic Neurons: A Potential Implication for the Development of Parkinson's Disease
| Autoři | |
|---|---|
| Rok publikování | 2025 |
| Druh | Článek v odborném periodiku |
| Časopis / Zdroj | ACS Chemical Biology |
| Fakulta / Pracoviště MU | |
| Citace | |
| www | https://pubs.acs.org/doi/10.1021/acschembio.4c00777# |
| Doi | https://doi.org/10.1021/acschembio.4c00777 |
| Klíčová slova | Carbohydrates; Inflammation; Nervous system diseases; Peptides and proteins; Rodent models |
| Přiložené soubory | |
| Popis | Accumulation of misfolded ?-synuclein (?-Syn) leads to the formation of Lewy bodies and is a major hallmark of Parkinson’s disease (PD). The accumulation of ?-Syn involves several post-translational modifications. Recently, though, glycation of ?-Syn (advanced glycation end products) and activation of the receptor for advanced glycation end products (RAGE) have been linked to neuroinflammation, which leads to oxidative stress and accumulation of ?-Syn. The present study aims to detect the effect of glycated ?-Syn (gly-?-Syn)-induced synucleinopathy and loss of dopaminergic (DAergic) neurons in the development of PD. We isolated, purified, and prepared glycated recombinant human ?-Syn using d-ribose. Gly-?-Syn was characterized by SDS-PAGE, intact mass analysis, and bottom-up peptide sequence through LC-HRMS/MS. The aggregation propensity of gly-?-Syn has been verified by morphological and shape analysis through Bio-AFM. The gly-?-Syn (2 µg/µL) was injected stereotaxically in the substantia nigra (SN) of ICR mice (3–4 months) and compared with the normal ?-Syn, d ribose, and Tris-HCl/artificial CSF groups. 56 days postsurgery (DPS), an immunohistochemical examination was conducted to investigate gly-?-Syn-induced ?-Syn accumulation, neuroinflammation, and neurodegeneration. The glycation of ?-Syn led to the expression of transglutaminase 2 (TGM2), an enzyme that cross-linked with AGEs and may have caused the accumulation of ?-Syn. Significant RAGE activation was also observed in gly-?-Syn, which might have induced glial cell activation, resulting in oxidative stress and, ultimately, apoptosis of dopaminergic neurons. It is important to note that TGM2, phosphorylated ?-Syn, RAGE expression, and glial cell activation were only found in the gly-?-Syn group and not in the other groups. This suggests that gly-?-Syn plays a major role in synucleinopathy, neuroinflammation, and neurodegeneration. Overall, the present study demonstrated glycation of ?-Syn as one of the important age-associated post-translational modifications that are involved in the degeneration of dopaminergic neurons, at least in a subset of the diabetic patients susceptible to developing PD. |
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