ArticleAutophagy2015
GBA deficiency promotes SNCA/α-synuclein accumulation through autophagic inhibition by inactivated PPP2A.
Article in Autophagy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers, 1 of them a synthesis that pooled it.
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Who cites it
76 citing papers in PubMed, 1 synthesis or guideline pooled it, 130 citations in OpenAlex.
- Sphingolipids in Gaucher disease: a systematic review.Orphanet journal of rare diseases · 2025Pooled it
- Review
- Protein phosphatase 2A methylation state impacts α-synucleinopathy in mouse models.Cell death discovery · 2026Article
- Constraint-based modelling of metabolic dysregulation in Gaucher disease: mitochondrial dysfunction and disrupted cholesterol homeostasis.Orphanet journal of rare diseases · 2026Article
- Glucosylceramides trigger the shedding of alpha-synuclein laden ectosomes.Extracellular vesicles and circulating nucleic acids · 2026Article
- GBA1 Gene-Associated Transcriptomic Signatures Reveal Risk Genes in Parkinson's Disease.Biomedicines · 2025Article
- Houge-Janssens syndrome.European journal of human genetics : EJHG · 2025Review
- Elevated hexosylceramides in Parkinson's disease cause gene upregulations in neurons mimicking responses to pathogens.NPJ Parkinson's disease · 2025Article
- Using network toxicology and molecular docking to identify core targets and pathways underlying tacrolimus-induced tremor in organ transplant recipients.Scientific reports · 2025Article
- A novel allosteric GCase modulator prevents Tau accumulation in GBA1Scientific reports · 2025Article
- Unifying biology of neurodegeneration in lysosomal storage diseases.Journal of inherited metabolic disease · 2025Review
- Differential gene expression patterns in Niemann-Pick Type C and Tay-Sachs diseases: Implications for neurodegenerative mechanisms.PloS one · 2025Article
- GBA-AAV mitigates sleep disruptions and motor deficits in mice with REM sleep behavior disorder.NPJ Parkinson's disease · 2024Article
- Novel and experimental therapeutics for the management of motor and non-motor Parkinsonian symptoms.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Review
- ENGINEERED NANOBODIES WITH PROGRAMMABLE TARGET ANTIGEN PROTEOLYSIS (PTAP) FUSIONS REGULATE INTRACELLULAR ALPHA-SYNUCLEIN IN VITRO AND IN VIVO.Research square · 2024Article
- Review
- Tau accumulation in degradative organelles is associated to lysosomal stress.Scientific reports · 2023Article
- Autophagy in Parkinson's Disease.Biomolecules · 2023Review
- GBA1 Variants and Parkinson's Disease: Paving the Way for Targeted Therapy.Journal of movement disorders · 2023Article
- Review
16 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Loss-of-function mutations in the gene encoding GBA (glucocerebrosidase, β, acid), the enzyme deficient in the lysosomal storage disorder Gaucher disease, elevate the risk of Parkinson disease (PD), which is characterized by the misprocessing of SNCA/α-synuclein. However, the mechanistic link between GBA deficiency and SNCA accumulation remains poorly understood. In this study, we found that loss of GBA function resulted in increased levels of SNCA via inhibition of the autophagic pathway in SK-N-SH neuroblastoma cells, primary rat cortical neurons, or the rat striatum. Furthermore, expression of the autophagy pathway component BECN1 was downregulated as a result of the GBA knockdown-induced decrease in glucocerebrosidase activity. Most importantly, inhibition of autophagy by loss of GBA function was associated with PPP2A (protein phosphatase 2A) inactivation via Tyr307 phosphorylation. C2-ceramide (C2), a PPP2A agonist, activated autophagy in GBA-silenced cells, while GBA knockdown-induced SNCA accumulation was reversed by C2 or rapamycin (an autophagy inducer), suggesting that PPP2A plays an important role in the GBA knockdown-mediated inhibition of autophagy. These findings demonstrate that loss of GBA function may contribute to SNCA accumulation through inhibition of autophagy via PPP2A inactivation, thereby providing a mechanistic basis for the increased PD risk associated with GBA deficiency.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.