气候变化领域集成服务门户(CCPortal): Wild-type GBA1 increases the α-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice

CCPortal

DOI	10.1073/pnas.2103425118
	Wild-type GBA1 increases the α-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice
	Glajch K.E.; Moors T.E.; Chen Y.; Bechade P.A.; Nam A.Y.; Rajsombath M.M.; McCaffery T.D.; Dettmer U.; Weihofen A.; Hirst W.D.; Selkoe D.J.; Nuber S.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:31
英文摘要	Loss-of-function mutations in acid beta-glucosidase 1 (GBA1) are among the strongest genetic risk factors for Lewy body disorders such as Parkinson's disease (PD) and Lewy body dementia (DLB). Altered lipid metabolism in PD patient-derived neurons, carrying either GBA1 or PD αS mutations, can shift the physiological α-synuclein (αS) tetramer-monomer (T:M) equilibrium toward aggregation-prone monomers. A resultant increase in pSer129+ αS monomers provides a likely building block for αS aggregates. 3K αS mice, representing a neuropathological amplification of the E46K PD-causing mutation, have decreased αS T:M ratios and vesicle-rich αS+ aggregates in neurons, accompanied by a striking PD-like motor syndrome. We asked whether enhancing glucocerebrosidase (GCase) expression could benefit αS dyshomeostasis by delivering an adeno-associated virus (AAV)-human wild-type (wt) GBA1 vector into the brains of 3K neonates. Intracerebroventricular AAV-wtGBA1 at postnatal day 1 resulted in prominent forebrain neuronal GCase expression, sustained through 6 mo. GBA1 attenuated behavioral deficits both in working memory and fine motor performance tasks. Furthermore, wtGBA1 increased αS solubility and the T:M ratio in both 3K-GBA mice and control littermates and reduced pS129+ and lipid-rich aggregates in 3K-GBA. We observed GCase distribution in more finely dispersed lysosomes, in which there was increased GCase activity, lysosomal cathepsin D and B maturation, decreased perilipin-stabilized lipid droplets, and a normalized TFEB translocation to the nucleus, all indicative of improved lysosomal function and lipid turnover. Therefore, a prolonged increase of the αS T:M ratio by elevating GCase activity reduced the lipid- and vesicle-rich aggregates and ameliorated PD-like phenotypes in mice, further supporting lipid modulating therapies in PD. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Cathepsin; GBA; Glucosylcerebrosidase; Tetramer; α-synuclein
语种	英语
scopus关键词	alpha synuclein; glucosylceramidase; lipid; recombinant protein; animal; chemistry; gene expression regulation; genetics; lipid metabolism; maze test; metabolism; motor activity; mouse; newborn; physiology; alpha-Synuclein; Animals; Animals, Newborn; Gene Expression Regulation, Enzymologic; Glucosylceramidase; Lipid Metabolism; Lipids; Maze Learning; Mice; Motor Activity; Recombinant Proteins
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251089
作者单位	Neurodegenerative Diseases Research Unit, Biogen, Cambridge, MA 02142, United States; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, United States
推荐引用方式 GB/T 7714	Glajch K.E.,Moors T.E.,Chen Y.,et al. Wild-type GBA1 increases the α-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice[J],2021,118(31).
APA	Glajch K.E..,Moors T.E..,Chen Y..,Bechade P.A..,Nam A.Y..,...&Nuber S..(2021).Wild-type GBA1 increases the α-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice.Proceedings of the National Academy of Sciences of the United States of America,118(31).
MLA	Glajch K.E.,et al."Wild-type GBA1 increases the α-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice".Proceedings of the National Academy of Sciences of the United States of America 118.31(2021).