ArticleProceedings of the National Academy of Sciences of the United States of America2014
LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers, 1 of them a synthesis that pooled it.
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Who cites it
74 citing papers in PubMed, 1 synthesis or guideline pooled it, 126 citations in OpenAlex.
- Emerging links between pediatric lysosomal storage diseases and adult parkinsonism.Movement disorders : official journal of the Movement Disorder Society · 2019Pooled it
- Elevated hexosylceramides in Parkinson's disease cause gene upregulations in neurons mimicking responses to pathogens.NPJ Parkinson's disease · 2025Article
- Canonical and noncanonical autophagy: involvement in Parkinson's disease.Frontiers in cell and developmental biology · 2025Review
- Gut dysbiosis impairs intestinal renewal and lipid absorption in Scarb2 deficiency-associated neurodegeneration.Protein & cell · 2024Article
- α-Synuclein: Multiple pathogenic roles in trafficking and proteostasis pathways in Parkinson's disease.The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2024Review
- Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson's disease.Translational neurodegeneration · 2024Review
- Lysosome quality control in health and neurodegenerative diseases.Cellular & molecular biology letters · 2024Review
- 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
- Deficiency of Glucocerebrosidase Activity beyond Gaucher Disease: PSAP and LIMP-2 Dysfunctions.International journal of molecular sciences · 2024Article
- Single-domain antibody-based protein degrader for synucleinopathies.Molecular neurodegeneration · 2024Article
- Single-Domain Antibody-Based Protein Degrader for Synucleinopathies.bioRxiv : the preprint server for biology · 2024Article
- Article
- Lysosomal membrane integrity in fibroblasts derived from patients with Gaucher disease.Cell structure and function · 2024Article
- Cerebrospinal fluid exploratory proteomics and ketamine metabolite pharmacokinetics in human volunteers after ketamine infusion.iScience · 2023Article
- GBA1 Variants and Parkinson's Disease: Paving the Way for Targeted Therapy.Journal of movement disorders · 2023Article
- Article
- Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein neurotoxicity.PLoS genetics · 2023Article
- SCAV-3 affects apoptotic cell degradation in Caenorhabditis elegans.FEBS open bio · 2023Article
- Advances in Drug Discovery Targeting Lysosomal Membrane Proteins.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Review
14 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 7 institutions in 3 countries.
Funding
Abstract
Mutations within the lysosomal enzyme β-glucocerebrosidase (GC) result in Gaucher disease and represent a major risk factor for developing Parkinson disease (PD). Loss of GC activity leads to accumulation of its substrate glucosylceramide and α-synuclein. Since lysosomal activity of GC is tightly linked to expression of its trafficking receptor, the lysosomal integral membrane protein type-2 (LIMP-2), we studied α-synuclein metabolism in LIMP-2-deficient mice. These mice showed an α-synuclein dosage-dependent phenotype, including severe neurological impairments and premature death. In LIMP-2-deficient brains a significant reduction in GC activity led to lipid storage, disturbed autophagic/lysosomal function, and α-synuclein accumulation mediating neurotoxicity of dopaminergic (DA) neurons, apoptotic cell death, and inflammation. Heterologous expression of LIMP-2 accelerated clearance of overexpressed α-synuclein, possibly through increasing lysosomal GC activity. In surviving DA neurons of human PD midbrain, LIMP-2 levels were increased, probably to compensate for lysosomal GC deficiency. Therefore, we suggest that manipulating LIMP-2 expression to increase lysosomal GC activity is a promising strategy for the treatment of synucleinopathies.
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Registered trials
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.