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α-Synuclein arginylation in the human brain

Translational Neurodegeneration 2022年第1期11卷 654-666页

作者： Jun Zhao Buyan pan Marie Fina Yun Huang Marie Shimogawa Kelvin C.Luk Elizabeth Rhoades ejames p.tersson Dawei W.Dong Anna Kashina Department of Biomedical Sciences University of Pennsylvania School of Veterinary MedicinePhiladelphiaPennsylvania 19104USA Department of Chemistry University of Pennsylvania School of Arts and SciencesPhiladelphiaPennsylvania 19104USA Center for Neurodegenerative Disease Research Department of Pathology and Laboratory MedicineUniversity of Pennsylvania Perelman School of MedicinePhiladelphiaPennsylvania 19104USA.

Background: Alpha-synuclein (α-syn) exhibits pathological misfolding in many human neurodegenerative disorders. We previously showed that α-syn is arginylated in the mouse brain and that lack of arginylation leads to neurodegen-eration in mice. Methods: Here, we tested α-syn arginylation in human brain pathology using newly derived antibodies in combina-tion with Western blotting, biochemical assays, and experiments in live neurons. Results: We found that α-syn was arginylated in the human brain on E46 and E83, two sites previously implicated in α-syn pathology and familial cases of parkinson’s disease. The levels of arginylation in different brain samples ranged between ~ 3% and ~ 50% of the total α-syn pool, and this arginylation nearly exclusively concentrated in the subcellu-lar α-syn fraction that sedimented at low centrifugation speeds and appeared to be simultaneously targeted by multi-ple posttranslational modifications. Arginylated α-syn was less susceptible to S129 phosphorylation and pathological aggregation in neurons. The arginylation level inversely correlated with the overall α-syn levels and with patient age, suggesting a possible causal relationship between arginylation decline and α-syn-dependent neuropathology. Conclusion: We propose that α-syn arginylation constitutes a potential neuroprotective mechanism that prevents its abnormal accumulation during neurodegeneration and aging in the human brain.

关键词： Arginylation Neurodegeneration Aging α-Synuclein

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