Two C-terminal sequence variations determine differential neurotoxicity between human and mouse α-synuclein.
Natalie LandeckKatherine E StrathearnDaniel YsselsteinKerstin BuckSayan DuttaSiddhartha BanerjeeZhengjian LvJohn D HullemanJagadish HindupurLi-Kai LinSonal PadalkarLia A StanciuYuri L LyubchenkoDeniz KirikJean-Christophe RochetPublished in: Molecular neurodegeneration (2020)
Mouse aSyn is less neurotoxic than the human A53T variant as a result of inhibitory effects of two C-terminal amino acid substitutions on membrane-induced aSyn aggregation and aSyn-mediated vesicle permeabilization. Our findings highlight the importance of membrane-induced self-assembly in aSyn neurotoxicity and suggest that inhibiting this process by targeting the C-terminal domain could slow neurodegeneration in PD and other synucleinopathy disorders.