ArticleMolecular neurobiology2014
Overexpression of human E46K mutant α-synuclein impairs macroautophagy via inactivation of JNK1-Bcl-2 pathway.
Article in Molecular neurobiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 51 citations in OpenAlex.
- Genetics of α-Synuclein: The Prime Pathological Player of Parkinson's Disease.Neurotoxicity research · 2026Review
- Targeting the Interplay Between Autophagy and the Nrf2 Pathway in Parkinson's Disease with Potential Therapeutic Implications.Biomolecules · 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
- Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations.International journal of molecular sciences · 2024Review
- Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy.Neurobiology of disease · 2023Article
- Autophagy and autophagy-related molecules in neurodegenerative diseases.Animal models and experimental medicine · 2023Review
- The Emerging Roles of Autophagy in Human Diseases.Biomedicines · 2021Review
- Selectivity of Lewy body protein interactions along the aggregation pathway of α-synuclein.Communications biology · 2021Article
- Neurons and Glia Interplay in α-Synucleinopathies.International journal of molecular sciences · 2021Review
- Protein Quality Control Pathways at the Crossroad of Synucleinopathies.Journal of Parkinson's disease · 2020Review
- Current Evidence for a Bidirectional Loop Between the Lysosome and Alpha-Synuclein Proteoforms.Frontiers in cell and developmental biology · 2020Review
- In Search of Effective Treatments Targeting α-Synuclein Toxicity in Synucleinopathies: Pros and Cons.Frontiers in cell and developmental biology · 2020Review
- Review
- A30P mutant α-synuclein impairs autophagic flux by inactivating JNK signaling to enhance ZKSCAN3 activity in midbrain dopaminergic neurons.Cell death & disease · 2019Article
- Crosstalk between presynaptic trafficking and autophagy in Parkinson's disease.Neurobiology of disease · 2019Review
- E46K Mutant α-Synuclein Is Degraded by Both Proteasome and Macroautophagy Pathway.Molecules (Basel, Switzerland) · 2018Article
- Cellular and Molecular Basis of Neurodegeneration in Parkinson Disease.Frontiers in aging neuroscience · 2018Review
- Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications.Frontiers in aging neuroscience · 2018Review
- mTOR Signaling in Parkinson's Disease.Neuromolecular medicine · 2017Review
- Enhancing lysosomal biogenesis and autophagic flux by activating the transcription factor EB protects against cadmium-induced neurotoxicity.Scientific reports · 2017Article
Corrections and comments
- Erratum issued
Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Parkinson's disease (PD) is pathologically characterized by selective loss of dopaminergic neurons in the midbrain and the existence of intracellular protein inclusions termed Lewy bodies, largely composed of α-synuclein. Genetic studies have revealed that rare point mutations in the gene encoding α-synuclein including A30P, A53T, and E46K are associated with familial forms of PD, indicating a pathological role for mutant α-synuclein in PD etiology. However, the mechanisms underlying the neuronal toxicity of mutant α-synuclein are still to be elucidated. Growing evidence has suggested a deleterious effect of mutant α-synuclein on the autophagy-lysosome pathway. In this study, we discovered that overexpression of human E46K mutant α-synuclein impaired macroautophagy in mammalian cells. Our data showed that overexpression of E46K mutant α-synuclein impaired autophagy at an early stage of autophagosome formation via the c-Jun N-terminal kinase 1 (JNK1)-Bcl-2 but not the mammalian target of rapamycin (mTOR) pathway. Overexpressed E46K mutant α-synuclein inhibited JNK1 activation, leading to a reduced Bcl-2 phosphorylation and increased association between Bcl-2 and Beclin1, further disrupting the formation of Beclin1/hVps34 complex, which is essential for autophagy initiation. Furthermore, overexpression of E46K mutant α-synuclein increased the vulnerability of differentiated PC12 cells to rotenone treatment, which would be partly due to its inhibitory effects on autophagy. Our findings may shed light on the potential roles of mutant α-synuclein in the pathogenesis of PD.
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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.