ArticleHuman molecular genetics2015
Potentiation of neurotoxicity in double-mutant mice with Pink1 ablation and A53T-SNCA overexpression.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers, 1 of them a synthesis that pooled it.
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Who cites it
41 citing papers in PubMed, 1 synthesis or guideline pooled it, 70 citations in OpenAlex.
- Parkinson's Disease is Associated with Dysregulations of a Dopamine-Modulated Gene Network Relevant to Sleep and Affective Neurobehaviors in the Striatum.Scientific reports · 2019Pooled it
- Species-dependent activities of the PINK1-parkin axis.Translational neurodegeneration · 2026Review
- Modest improvement of metabolic and behavioral deficits with long-term ambroxol treatment in a Pink1Acta pharmacologica Sinica · 2026Article
- Cardiolipin and mitochondrial membrane integrity in neurodegeneration: insights from α-synuclein-driven Parkinson's disease.Acta neuropathologica communications · 2025Review
- Elevated hexosylceramides in Parkinson's disease cause gene upregulations in neurons mimicking responses to pathogens.NPJ Parkinson's disease · 2025Article
- Experimental and computational insights into the therapeutic mechanisms of resveratrol in a Drosophila α-synuclein model of Parkinson's disease.Scientific reports · 2025Article
- Liquid-liquid phase separation and conformational strains ofFrontiers in molecular neuroscience · 2024Review
- Involvement of Mitochondria in Parkinson's Disease.International journal of molecular sciences · 2023Review
- Alpha-synuclein-associated changes in PINK1-PRKN-mediated mitophagy are disease context dependent.Brain pathology (Zurich, Switzerland) · 2023Article
- Outlook of PINK1/Parkin signaling in molecular etiology of Parkinson's disease, with insights intoZoological research · 2023Review
- Whole-blood methylation signatures are associated with and accurately classify multiple sclerosis disease severity.Clinical epigenetics · 2022Article
- Fat and Protein Combat Triggers Immunological Weapons of Innate and Adaptive Immune Systems to Launch Neuroinflammation in Parkinson's Disease.International journal of molecular sciences · 2022Review
- PTEN-Induced Putative Kinase 1 Dysfunction Accelerates Synucleinopathy.Journal of Parkinson's disease · 2022Article
- Review
- Failure of Diphtheria Toxin Model to Induce Parkinson-Like Behavior in Mice.International journal of molecular sciences · 2021Article
- Longitudinal tracking of neuronal mitochondria delineates PINK1/Parkin-dependent mechanisms of mitochondrial recycling and degradation.Science advances · 2021Article
- Genes Implicated in Familial Parkinson's Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage.International journal of molecular sciences · 2021Review
- Aging and pathological aging signatures of the brain: through the focusing lens of SIRT6.Aging · 2021Article
- Epigenetic gene expression links heart failure to memory impairment.EMBO molecular medicine · 2021Article
- Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The common age-related neurodegeneration of Parkinson's disease can result from dominant causes like increased dosage of vesicle-associated alpha-synuclein (SNCA) or recessive causes like deficiency of mitophagy factor PINK1. Interactions between these triggers and their convergence onto shared pathways are crucial, but currently conflicting evidence exists. Here, we crossed previously characterized mice with A53T-SNCA overexpression and with Pink1 deletion to generate double mutants (DMs). We studied their lifespan and behavior, histological and molecular anomalies at late and early ages. DM animals showed potentiated phenotypes in comparison with both single mutants (SMs), with reduced survival and strongly reduced spontaneous movements from the age of 3 months onwards. In contrast to SMs, a quarter of DM animals manifested progressive paralysis at ages >1 year and exhibited protein aggregates immunopositive for pSer129-SNCA, p62 and ubiquitin in spinal cord and basal brain. Brain proteome quantifications of ubiquitination sites documented altered degradation of SNCA and the DNA-damage marker H2AX at the age of 18 months. Global brain transcriptome profiles and qPCR validation experiments identified many consistent transcriptional dysregulations already at the age of 6 weeks, which were absent from SMs. The observed downregulations for Dapk1, Dcaf17, Rab42 and the novel SNCA-marker Lect1 as well as the upregulations for Dctn5, Mrpl9, Tmem181a, Xaf1 and H2afx reflect changes in ubiquitination, mitochondrial/synaptic/microtubular/cell adhesion dynamics and DNA damage. Thus, our study confirmed that SNCA-triggered neurotoxicity is exacerbated by the absence of PINK1 and identified a novel molecular signature that is detectable early in the course of this double pathology.
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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.