Wild-type GBA1 increases the α-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice

被引：23

作者：

Glajch, Kelly E. ^{[1
]}

Moors, Tim E. ^{[2
]}

Chen, Yi ^{[1
]}

Bechade, Pascal A. ^{[2
]}

Nam, Alice Y. ^{[2
]}

Rajsombath, Molly M. ^{[2
]}

McCaffery, Thomas D. ^{[2
]}

Dettmer, Ulf ^{[2
]}

Weihofen, Andreas ^{[1
]}

Hirst, Warren D. ^{[1
]}

Selkoe, Dennis J. ^{[2
]}

Nuber, Silke ^{[2
]}

机构：

[1] Biogen, Neurodegenerat Dis Res Unit, Cambridge, MA 02142 USA

[2] Harvard Med Sch, Ann Romney Ctr Neurol Dis, Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2021年 / 118卷 / 31期

关键词：

alpha-synuclein; tetramer; glucosylcerebrosidase; cathepsin; GBA; STEAROYL-COA DESATURASE; PARKINSONS-DISEASE; GLUCOCEREBROSIDASE MUTATIONS; GAUCHER-DISEASE; CATHEPSIN-D; ACTIVATION; PHENOTYPE; MULTIMERS; AUTOPHAGY; REVEALS;

D O I：

10.1073/pnas.2103425118

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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 alpha S mutations, can shift the physiological alpha-synuclein (alpha S) tetramer-monomer (T:M) equilibrium toward aggregation-prone monomers. A resultant increase in pSer129+ alpha S monomers provides a likely building block for alpha S aggregates. 3K alpha S mice, representing a neuropathological amplification of the E46K PD-causing mutation, have decreased alpha S T:M ratios and vesicle-rich alpha S+ aggregates in neurons, accompanied by a striking PD-like motor syndrome. We asked whether enhancing glucocerebrosidase (GCase) expression could benefit alpha S 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 alpha S 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 perilipinstabilized 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 alpha S 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.

引用

页数：10