Brain——α-Synuclein糖基化加剧synucleinopathies的神经变性

摘要

a-Synuclein misfolding and aggregation is a hallmark in Parkinson’s disease and in several other neurodegenerative diseases known as synucleinopathies. The toxic properties of a-synuclein are conserved from yeast to man, but the precise underpinnings of the cellular pathologies associated are still elusive, complicating the development of effective therapeutic strategies. Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced a-synuclein toxicity in vitro and in vivo, in Drosophila and in mice. Glycation affected primarily the N-terminal region of a-synuclein, reducing membrane binding, impaired the clearance of a-synuclein, and promoted the accumulation of toxic oligomers that impaired neuronal synaptic transmission. Strikingly, using glycation inhibitors, we demonstrated that normal clearance of a-synuclein was re-established, aggregation was reduced, and motor phenotypes in Drosophila were alleviated. Altogether, our study demonstrates glycation constitutes a novel drug target that can be explored in synucleinopathies as well as in other neurodegenerative conditions.

主要结果一Glo1和TPi的敲减增加糖基化并降低生存率

主要结果二：MGO通过影响蛋白酶体和自噬功能促进α-Synuclein毒性

主要结果三：MGO清除剂减少α-Synuclein病变，改善运动功能

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