ArticleMolecules (Basel, Switzerland)2018
E46K Mutant α-Synuclein Is Degraded by Both Proteasome and Macroautophagy Pathway.
Article in Molecules (Basel, Switzerland), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 20 citations in OpenAlex.
- RNF167 mediates atypical ubiquitylation and degradation of RLRs via two distinct proteolytic pathways.Nature communications · 2025Article
- The interplay between physical exercise and autophagy signaling in brain health, neurodegenerative diseases and aging.Frontiers in aging neuroscience · 2025Review
- E46K α-Synuclein Mutation Fails to Promote Neurite Outgrowth by Not Inducing Cdc42EP2 Expression, Unlike Wild-Type or A53T α-Synuclein in SK-N-SH Cells.Brain sciences · 2024Article
- Review
- MicroRNAs regulating autophagy: opportunities in treating neurodegenerative diseases.Frontiers in neuroscience · 2024Review
- Review
- Exploring the Role of Autophagy Dysfunction in Neurodegenerative Disorders.Molecular neurobiology · 2021Review
- Autophagy in Neurodegenerative Diseases: A Hunter for Aggregates.International journal of molecular sciences · 2020Review
- Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies.International journal of molecular sciences · 2020Review
- Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms.Frontiers in cell and developmental biology · 2020Review
- LRRK2 Kinase Inhibition Rescues Deficits in Lysosome Function Due to HeterozygousFrontiers in neuroscience · 2020Article
- Review
- Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Genetic studies have revealed that rare mutations and multiplications of the gene locus in α-synuclein (α-syn) are implicated in the pathogenesis of Parkinson's disease (PD). However, the pathological effects of α-syn are still obscure. The neurotoxicity of α-syn is mainly determined by its protein levels, which depend on a balance between synthesis and degradation. Therefore, verifying the possible routes contributing to the clearance of α-syn is important for PD therapy. In this study, we established stable lines overexpressing human wild-type (WT) and E46K mutant α-syn in rat PC12 cells and investigated the degradation pathways of α-syn by using a panel of inhibitors and inducers of lysosome and proteasome function. We also monitored the degradation kinetics of α-syn by using cycloheximide to block protein synthesis. Our data showed that both proteasome and chaperon-mediated autophagy (CMA) are responsible for the degradation of the WT α-syn. Meanwhile, E46K mutant α-syn is mainly degraded by the proteasome and macroautophagy pathway. Compared with the WT protein, E46K mutant α-syn turned over more slowly in PC12 cells. In addition, overexpression of E46K mutant α-syn increased vulnerability of PC12 cells to apoptosis insults when compared with WT α-syn. Our findings may verify the possible routes contributing to the degradation of the E46K mutant α-syn.
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