ArticleEMBO molecular medicine2017
Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases.
Article in EMBO molecular medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 1 of them a synthesis that pooled it.
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Who cites it
58 citing papers in PubMed, 1 synthesis or guideline pooled it, 79 citations in OpenAlex.
- Selective autophagy of intracellular organelles: recent research advances.Theranostics · 2021Pooled it
- Synaptic Proteostasis in Health and Disease.Journal of neurochemistry · 2026Review
- ExIR enables prioritizing driver and biomarker genes from omics data in a reference free manner.iScience · 2026Article
- Ultrastructural studies reveal a new role for JIP3/MAPK8IP3 in endo-lysosomal maturation within the neuronal cell body.Molecular biology of the cell · 2026Article
- Short-Term Oral Spermidine Supplementation Modifies Aspects of Neurodegenerative Disease in Flies and Mice With MPS III.Journal of inherited metabolic disease · 2026Article
- Modelling synaptic dysfunction in childhood dementia using human iPSC-derived cortical networks.Nature communications · 2026Article
- Impaired docking and recycling of synaptic vesicles in inherited lysosomal sphingolipidoses.Cell communication and signaling : CCS · 2025Article
- Alzheimer's genetic risk factor Bin1 controls synapse vesicle exo-endocytosis in inhibitory synapses.Cell reports · 2025Article
- D1 dopamine receptor antagonists as a new therapeutic strategy to treat autistic-like behaviours in lysosomal storage disorders.Molecular psychiatry · 2025Article
- Unifying biology of neurodegeneration in lysosomal storage diseases.Journal of inherited metabolic disease · 2025Review
- Cysteine string protein α and a link between rare and common neurodegenerative dementias.NPJ dementia · 2025Review
- Loss of two-pore channel 2 enhances CD8+ T cell cytotoxicity and directly impairs tumour growth via MAPK axis in HCC.Frontiers in immunology · 2025Article
- Scutellarin ameliorates ischemia/reperfusion-mediated endothelial dysfunction by upregulating cathepsin D expression to rescue autophagy-lysosomal function.Frontiers in pharmacology · 2025Article
- Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer's disease-relevant brain circuits.Nature communications · 2024Article
- Anti-amyloid treatment is broadly effective in neuronopathic mucopolysaccharidoses and synergizes with gene therapy in MPS-IIIA.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Redox Imbalance in Neurological Disorders in Adults and Children.Antioxidants (Basel, Switzerland) · 2023Review
- Molecular Tweezers: Supramolecular Hosts with Broad-Spectrum Biological Applications.Pharmacological reviews · 2023Review
- Decreased Levels of Chaperones in Mucopolysaccharidoses and Their Elevation as a Putative Auxiliary Therapeutic Approach.Pharmaceutics · 2023Article
- Age-Related Changes of the Synucleins Profile in the Mouse Retina.Biomolecules · 2023Article
- Development of Lanzyme as the Potential Enzyme Replacement Therapy Drug for Fabry Disease.Biomolecules · 2022Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Lysosomal storage disorders (LSDs) are inherited diseases characterized by lysosomal dysfunction and often showing a neurodegenerative course. There is no cure to treat the central nervous system in LSDs. Moreover, the mechanisms driving neuronal degeneration in these pathological conditions remain largely unknown. By studying mouse models of LSDs, we found that neurodegeneration develops progressively with profound alterations in presynaptic structure and function. In these models, impaired lysosomal activity causes massive perikaryal accumulation of insoluble α-synuclein and increased proteasomal degradation of cysteine string protein α (CSPα). As a result, the availability of both α-synuclein and CSPα at nerve terminals strongly decreases, thus inhibiting soluble NSF attachment receptor (SNARE) complex assembly and synaptic vesicle recycling. Aberrant presynaptic SNARE phenotype is recapitulated in mice with genetic ablation of one allele of both CSPα and α-synuclein. The overexpression of CSPα in the brain of a mouse model of mucopolysaccharidosis type IIIA, a severe form of LSD, efficiently re-established SNARE complex assembly, thereby ameliorating presynaptic function, attenuating neurodegenerative signs, and prolonging survival. Our data show that neurodegenerative processes associated with lysosomal dysfunction may be presynaptically initiated by a concomitant reduction in α-synuclein and CSPα levels at nerve terminals. They also demonstrate that neurodegeneration in LSDs can be slowed down by re-establishing presynaptic functions, thus identifying synapse maintenance as a novel potentially druggable target for brain treatment in LSDs.
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