ArticleHuman molecular genetics2023
The GBA variant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in human cell lines.
Article in Human molecular genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 13 citations in OpenAlex.
- Cellular and systemic modifiers of alpha-synuclein proteostasis.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- E326KJournal of Parkinson's disease · 2026Article
- Article
- Lipid droplets promote aberrant liquid-liquid phase separation of alpha-synuclein impairing energy homeostasis.EMBO reports · 2026Article
- Hereditary spastic paraplegia (HSP) gene 11 (Spg11) attenuates lipid accumulation in myeloid cells and neuroinflammation in the midbrain without affecting α-synuclein pathology.Journal of neuroinflammation · 2026Article
- Multi-omics insights into GBA1-associated Parkinson's disease: interplay of genomics, transcriptomics, proteomics, and lipidomics.Molecular neurodegeneration · 2026Review
- Dairy-rich diet triggers hepatic α-synuclein pathology via the liver-brain axis in GBA1-related Parkinson's disease.NPJ Parkinson's disease · 2025Article
- Lipid droplets promote the aberrant liquid-liquid phase separation of alpha-synuclein leading to impaired energy homeostasis.bioRxiv : the preprint server for biology · 2025Article
- A Common PD-RiskbioRxiv : the preprint server for biology · 2025Article
- LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.Nature metabolism · 2025Article
- Stearoyl-CoA desaturase inhibition normalizes brain lipid saturation, α-synuclein homeostasis, and motor function in mutant Gba1-Parkinson mice.JCI insight · 2025Article
- Interplay between lipid droplets and alpha-synuclein: implication in Parkinson's disease pathogenesis.Frontiers in molecular neuroscience · 2025Review
- Gba1 E326K renders motor and non-motor symptoms with pathological α-synuclein, tau and glial activation.Brain : a journal of neurology · 2024Article
- Investigating the Impact of the Parkinson's-Associated GBA1 E326K Mutation on β-Glucocerebrosidase Dimerization and Interactome Dynamics Through an In Silico Approach.International journal of molecular sciences · 2024Article
- Gaucher disease provides a unique window into Parkinson disease pathogenesis.Nature reviews. Neurology · 2024Review
- RXR nuclear receptor signaling modulates lipid metabolism and triggers lysosomal clearance of alpha-synuclein in neuronal models of synucleinopathy.Cellular and molecular life sciences : CMLS · 2024Article
- Activation and Purification of ß-Glucocerebrosidase by Exploiting its Transporter LIMP-2 - Implications for Novel Treatment Strategies in Gaucher's and Parkinson's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Biochemical consequences ofNeural regeneration research · 2024Article
- Article
- The importance of being connected: membrane contact sites and Parkinson's disease.Neural regeneration research · 2023Article
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Authors and funding
5 authors at 2 institutions in 3 countries.
Funding
Abstract
Sequence variants or mutations in the GBA gene are numerically the most important risk factor for Parkinson disease (PD). The GBA gene encodes for the lysosomal hydrolase enzyme, glucocerebrosidase (GCase). GBA mutations often reduce GCase activity and lead to the impairment of the autophagy-lysosomal pathway, which is important in the turnover of alpha-synuclein, accumulation of which is a key pathological hallmark of PD. Although the E326K variant is one of the most common GBA variants associated with PD, there is limited understanding of its biochemical effects. We have characterized homozygous and heterozygous E326K variants in human fibroblasts. We found that E326K variants did not cause a significant loss of GCase protein or activity, endoplasmic reticulum (ER) retention or ER stress, in contrast to the L444P GBA mutation. This was confirmed in human dopaminergic SH-SY5Y neuroblastoma cell lines overexpressing GCase with either E326K or L444P protein. Despite no loss of the GCase activity, a significant increase in insoluble alpha-synuclein aggregates in E326K and L444P mutants was observed. Notably, SH-SY5Y overexpressing E326K demonstrated a significant increase in the lipid droplet number under basal conditions, which was exacerbated following treatment with the fatty acid oleic acid. Similarly, a significant increase in lipid droplet formation following lipid loading was observed in heterozygous and homozygous E326K fibroblasts. In conclusion, the work presented here demonstrates that the E326K mutation behaves differently to the common loss of function GBA mutations; however, lipid dyshomeostasis and alpha-synuclein pathology are still evident.
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