ArticleProceedings of the National Academy of Sciences of the United States of America2021
Wild-type GBA1 increases the α-synuclein tetramer-monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 40 citations in OpenAlex.
- Interplay of GBA1 with lysosomal dysfunction and inflammation in Parkinson's disease.Neural regeneration research · 2026Article
- Lipid membrane remodeling by myristic acid treatment reverses Parkinson's disease α-synuclein phenotypes in patient neurons.npj metabolic health and disease · 2026Article
- Biodistribution of AAV1, AAV5, AAV9, and AAVDJ serotypes after intra-cisterna magna delivery in non-human primates.Molecular therapy. Methods & clinical development · 2025Article
- Parkinson disease is a fatty acidopathy.Nature reviews. Neurology · 2025Review
- Progress in Disease-Modifying Therapies for Parkinson's Disease.Aging and disease · 2025Review
- The Search for Disease Modification in Parkinson's Disease-A Review of the Literature.Life (Basel, Switzerland) · 2025Review
- Stearoyl-CoA desaturase inhibition normalizes brain lipid saturation, α-synuclein homeostasis, and motor function in mutant Gba1-Parkinson mice.JCI insight · 2025Article
- A personalised and comprehensive approach is required to suppress or replenish SNCA for Parkinson's disease.NPJ Parkinson's disease · 2025Review
- Article
- Conformational Selection of α-Synuclein Tetramers at Biological Interfaces.Journal of chemical information and modeling · 2024Article
- Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Review
- Reducing the lipase LIPE in mutant α-synuclein mice improves Parkinson-like deficits and reveals sex differences in fatty acid metabolism.Neurobiology of disease · 2024Article
- Neither alpha-synuclein fibril strain nor host murine genotype influences seeding efficacy.NPJ Parkinson's disease · 2024Article
- Generation of G51D and 3D mice reveals decreased α-synuclein tetramer-monomer ratios promote Parkinson's disease phenotypes.NPJ Parkinson's disease · 2024Article
- Alpha-Synuclein Contribution to Neuronal and Glial Damage in Parkinson's Disease.International journal of molecular sciences · 2023Review
- GBA1 Variants and Parkinson's Disease: Paving the Way for Targeted Therapy.Journal of movement disorders · 2023Article
- Functional roles of sphingolipids in immunity and their implication in disease.Experimental & molecular medicine · 2023Review
- The Parkinson-Associated Toxin Paraquat Shifts Physiological α-Synuclein Tetramers toward Monomers That Can Be Calpain-Truncated and Form Oligomers.The American journal of pathology · 2023Article
- The GBA variant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in human cell lines.Human molecular genetics · 2023Article
- Genetic modifiers of synucleinopathies-lessons from experimental models.Oxford open neuroscience · 2023Review
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
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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