Open AccessWild-type GBA1 increases the α-synuclein tetramer–monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice
Author(s) -
Kelly E. Glajch,
Tim Moors,
Yi Chen,
Pascal A Bechade,
Alice Y Nam,
Molly M Rajsombath,
Thomas D. McCaffery,
Ulf Dettmer,
Andreas Weihofen,
Warren D. Hirst,
Dennis J. Selkoe,
Silke Nuber
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2103425118
Subject(s) - chemistry , glucocerebrosidase , lipid droplet , forebrain , alpha synuclein , endocrinology , medicine , dementia with lewy bodies , parkinson's disease , microbiology and biotechnology , biology , biochemistry , central nervous system , dementia , enzyme , disease
Significance The mechanisms responsible for brain α-synuclein (αS) dyshomeostasis, caused by Gaucher’s GBA1 mutations that increase Parkinson’s disease (PD) risk, are largely unknown. We previously showed that abrogating physiological αS tetramers by a familial PD-E46K–amplified 3K mutation produces PD-like syndrome in mice and that treatment with stearoyl-CoA desaturase inhibitors increased a portion of the αS tetramers, benefitting the motor phenotypes. Here, we show that—similar to previous findings in GBA1-mutant PD culture—GCase elevation prolonged the stabilization of wild-type and 3K mutant αS tetramers in wtGBA1–transduced mouse brains, improving lysosomal integrity and motor and cognitive phenotypes. These data help elucidating lipid modulators that impact the αS physiological state in vivo and the development of PD therapeutic approaches.