ArticleTranslational neurodegeneration2023
Reciprocal effects of alpha-synuclein aggregation and lysosomal homeostasis in synucleinopathy models.
Article in Translational neurodegeneration, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 40 citations in OpenAlex.
- Cellular and systemic modifiers of alpha-synuclein proteostasis.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- Ginsenoside Rg1, a Natural Lysosomal Enhancer, Alleviates Parkinson's Disease Pathology via Cathepsin D-Dependent Regulation of α-Synuclein Homeostasis.Phytotherapy research : PTR · 2026Article
- Lysine acetyltransferase 8-mediated histone acetylation, regulated by GBA1, is associated with lysosomal function related to α-Synuclein pathology.Cell death & disease · 2026Article
- Bibliometric analysis of nanomaterials in the diagnosis and treatment of neurological and psychiatric disorders (1997-2025): trends and future directions.Journal of nanobiotechnology · 2026Review
- Cell-based regenerative interventions in Parkinson's disease: Overcoming pharmacological limitations.Acta pharmaceutica Sinica. B · 2026Review
- ImpairedNature communications · 2026Article
- Microglia, Astrocytes, and Oligodendrocytes in Parkinson's Disease: Neuroinflammatory Crosstalk and Emerging Therapeutic Strategies.Biomolecules · 2026Review
- Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.Autophagy · 2026Review
- Research progress on the α-synuclein-lysosome axis in Parkinson's disease: molecular mechanisms of protein aggregation, autophagy dysfunction, and therapeutic targeting.Frontiers in neuroscience · 2026Review
- Autophagy-Lysosome Pathway Dysfunction in Neurodegeneration and Cancer: Mechanisms and Therapeutic Opportunities.International journal of molecular sciences · 2025Review
- Underlying Mechanisms of GBA1 in Parkinson's Disease and Dementia with Lewy Bodies: Narrative Review.Genes · 2025Review
- Long-term oral glucocerebrosidase activator reduces soluble α-synuclein oligomer accumulation in Parkinsonian LRRK2 mutant mouse brain.NPJ Parkinson's disease · 2025Article
- Dysregulated proteostasis in p.A53T-α-Synuclein astrocytes aggravates Lewy-like neuropathology in a Parkinson's disease iPSC model.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Induced Pluripotent Stem Cells Derived Cellular Models for Investigating Parkinson's Disease Pathogenesis and Drug Screening.Stem cell reviews and reports · 2025Review
- Recombinant cathepsins B and L promote α-synuclein clearance and restore lysosomal function in human and murine models with α-synuclein pathology.Molecular neurodegeneration · 2025Article
- Cathepsins in Neurological Diseases.International journal of molecular sciences · 2025Review
- The Parkinson Disease-Associated Mutant DNAJC13(N855S) Leads to Its Accelerated Degradation and Negatively Affects Macroautophagy and Retromer Complex-Mediated Dynamics.Journal of cellular physiology · 2025Article
- Metabolic Syndrome and Parkinson's Disease: Two Villains Join Forces.Brain sciences · 2025Article
- Vimentin network dysregulation mediates neurite deficits inScience advances · 2025Article
- Prioritizing Parkinson's disease risk genes in genome-wide association loci.NPJ Parkinson's disease · 2025Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundLysosomal dysfunction has been implicated in a number of neurodegenerative diseases such as Parkinson's disease (PD). Various molecular, clinical and genetic studies have highlighted a central role of lysosomal pathways and proteins in the pathogenesis of PD. Within PD pathology the synaptic protein alpha-synuclein (αSyn) converts from a soluble monomer to oligomeric structures and insoluble amyloid fibrils. The aim of this study was to unravel the effect of αSyn aggregates on lysosomal turnover, particularly focusing on lysosomal homeostasis and cathepsins. Since these enzymes have been shown to be directly involved in the lysosomal degradation of αSyn, impairment of their enzymatic capacity has extensive consequences.
methodsWe used patient-derived induced pluripotent stem cells and a transgenic mouse model of PD to examine the effect of intracellular αSyn conformers on cell homeostasis and lysosomal function in dopaminergic (DA) neurons by biochemical analyses.
resultsWe found impaired lysosomal trafficking of cathepsins in patient-derived DA neurons and mouse models with αSyn aggregation, resulting in reduced proteolytic activity of cathepsins in the lysosome. Using a farnesyltransferase inhibitor, which boosts hydrolase transport via activation of the SNARE protein ykt6, we enhanced the maturation and proteolytic activity of cathepsins and thereby decreased αSyn protein levels.
conclusionsOur findings demonstrate a strong interplay between αSyn aggregation pathways and function of lysosomal cathepsins. It appears that αSyn directly interferes with the enzymatic function of cathepsins, which might lead to a vicious cycle of impaired αSyn degradation. Lysosomal trafficking of cathepsin D (CTSD), CTSL and CTSB is disrupted when alpha-synuclein (αSyn) is aggregated. This results in a decreased proteolytic activity of cathepsins, which directly mediate αSyn clearance. Boosting the transport of the cathepsins to the lysosome increases their activity and thus contributes to efficient αSyn degradation.
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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.