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

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          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.

          Abstract

          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.

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          Most cited references66

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          Autophagy regulates lipid metabolism.

          The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.
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            Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.

            Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease. 2009 Massachusetts Medical Society
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              Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes

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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc Natl Acad Sci U S A
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                03 August 2021
                29 July 2021
                29 July 2021
                : 118
                : 31
                : e2103425118
                Affiliations
                [1] aNeurodegenerative Diseases Research Unit, Biogen , Cambridge, MA 02142;
                [2] bAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School , Boston, MA 02115
                Author notes
                1To whom correspondence may be addressed. Email: snuber@ 123456bwh.harvard.edu or dselkoe@ 123456bwh.harvard.edu .

                Edited by Anders Björklund, Lund University, Lund, Sweden, and approved June 11, 2021 (received for review February 19, 2021)

                Author contributions: K.E.G., T.E.M., and S.N. designed research; K.E.G., T.E.M., Y.C., P.A.B., A.Y.N., M.M.R., T.D.M., and S.N. performed research; K.E.G., T.E.M., Y.C., P.A.B., A.Y.N., M.M.R., T.D.M., and S.N. analyzed data; and K.E.G., T.E.M., P.A.B., U.D., A.W., W.D.H., D.J.S., and S.N. wrote the paper.

                Author information
                https://orcid.org/0000-0003-3705-7791
                https://orcid.org/0000-0002-9853-4005
                https://orcid.org/0000-0002-7633-6008
                https://orcid.org/0000-0001-6676-0107
                https://orcid.org/0000-0001-6265-9087
                https://orcid.org/0000-0003-0389-8891
                https://orcid.org/0000-0001-8846-9767
                https://orcid.org/0000-0002-2124-6865
                Article
                202103425
                10.1073/pnas.2103425118
                8346893
                34326260
                4ae09ef4-8372-4fc6-8b97-632038adaf95
                Copyright © 2021 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                History
                Page count
                Pages: 10
                Funding
                Funded by: HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) 100000065
                Award ID: NS099328
                Award Recipient : Ulf Dettmer Award Recipient : Dennis Selkoe Award Recipient : Silke Nuber
                Funded by: HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) 100000065
                Award ID: NS083845
                Award Recipient : Ulf Dettmer Award Recipient : Dennis Selkoe Award Recipient : Silke Nuber
                Funded by: HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) 100000065
                Award ID: NS109510
                Award Recipient : Ulf Dettmer Award Recipient : Dennis Selkoe Award Recipient : Silke Nuber
                Funded by: Women's Brain Initiative
                Award ID: Gift
                Award Recipient : Silke Nuber
                Categories
                424
                Biological Sciences
                Neuroscience

                α-synuclein,tetramer,glucosylcerebrosidase,cathepsin,gba
                α-synuclein, tetramer, glucosylcerebrosidase, cathepsin, gba

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