RT Journal Article
SR Electronic
T1 Two C-terminal sequence variations determine differential neurotoxicity between human and mouse α-synuclein
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 700377
DO 10.1101/700377
A1 Natalie Landeck
A1 Katherine E. Strathearn
A1 Daniel Ysselstein
A1 Kerstin Buck
A1 Sayan Dutta
A1 Siddhartha Banerjee
A1 Zhengjian Lv
A1 John D. Hulleman
A1 Jagadish Hindupur
A1 Li-Kai Lin
A1 Sonal Padalkar
A1 George P. McCabe
A1 Lia A. Stanciu
A1 Yuri L. Lyubchenko
A1 Deniz Kirik
A1 Jean-Christophess Rochet
YR 2019
UL http://biorxiv.org/content/early/2019/12/31/700377.abstract
AB α-Synuclein (aSyn) aggregation is thought to play a central role in neurodegenerative disorders termed synucleinopathies, including Parkinson’s disease (PD). Mouse aSyn contains a threonine residue at position 53 that mimics the human familial PD substitution A53T, yet in contrast to A53T patients, mice show no evidence of aSyn neuropathology even after aging. Here we studied the neurotoxicity of human A53T, mouse aSyn, and various human-mouse chimeras in cellular and in vivo models as well as their biochemical properties relevant to aSyn pathobiology. We report that 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.