ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2015
α-Synuclein-independent histopathological and motor deficits in mice lacking the endolysosomal Parkinsonism protein Atp13a2.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 96 citations in OpenAlex.
- Lysosomal dysfunction in neurodegenerative disease.Nature reviews. Neurology · 2026Review
- ATP13A4 gates extracellular polyamine levels to control excitatory synaptogenesis.Nature communications · 2026Article
- Strategies for Optimizing Genetic Mouse Models to Enhance the Understanding of Parkinson's Disease.Biomedicines · 2026Review
- ATP13A2 Loss of Function-Driven Polyamine Dysregulation Induces SAM Depletion and Epigenetic Astrocyte Toxicity.bioRxiv : the preprint server for biology · 2026Article
- Progress in modelling ATP13A2-linked neurodegeneration.NPJ Parkinson's disease · 2026Review
- Oxidative Stress-Related Serum Extracellular Vesicle miRNAs Indicate Symptom Severity and Cognitive Decline in Parkinson's Disease.Journal of neurochemistry · 2026Article
- Phenotypic characterization of an Atp13a2 knockout rat model of Parkinson's disease.NPJ Parkinson's disease · 2025Article
- Phenotype Differences Between ATP13A2 Heterozygous and Knockout Mice Across Aging.International journal of molecular sciences · 2025Article
- Aging, cellular senescence and Parkinson's disease.Journal of Parkinson's disease · 2025Review
- Depletion of ATP13A2 in adult brain induces a Parkinsonian phenotype in mice and non-human primates.NPJ Parkinson's disease · 2024Article
- Nigral ATP13A2 depletion induces Parkinson's disease-related neurodegeneration in a pilot study in non-human primates.NPJ Parkinson's disease · 2024Article
- Adult-onset deletion of ATP13A2 in mice induces progressive nigrostriatal pathway dopaminergic degeneration and lysosomal abnormalities.NPJ Parkinson's disease · 2024Article
- Recalibrating the Why and Whom of Animal Models in Parkinson Disease: A Clinician's Perspective.Brain sciences · 2024Review
- ATG8-dependent LMX1B-autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience.The Journal of cell biology · 2023Article
- ATP13A2 (PARK9) and basal ganglia function.Frontiers in neurology · 2023Review
- ATP13A2 Declines Zinc-Induced Accumulation of α-Synuclein in a Parkinson's Disease Model.International journal of molecular sciences · 2022Article
- Significant modulations of linc001128 and linc0938 with miR-24-3p and miR-30c-5p in Parkinson disease.Scientific reports · 2022Article
- Insulin-like growth factor 2 and autophagy gene expression alteration arise as potential biomarkers in Parkinson's disease.Scientific reports · 2022Article
- Glial Dysfunction and Its Contribution to the Pathogenesis of the Neuronal Ceroid Lipofuscinoses.Frontiers in neurology · 2022Review
- Autophagy in the Neuronal Ceroid Lipofuscinoses (Batten Disease).Frontiers in cell and developmental biology · 2022Review
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
Abstract
Accumulating evidence from genetic and biochemical studies implicates dysfunction of the autophagic-lysosomal pathway as a key feature in the pathogenesis of Parkinson's disease (PD). Most studies have focused on accumulation of neurotoxic α-synuclein secondary to defects in autophagy as the cause of neurodegeneration, but abnormalities of the autophagic-lysosomal system likely mediate toxicity through multiple mechanisms. To further explore how endolysosomal dysfunction causes PD-related neurodegeneration, we generated a murine model of Kufor-Rakeb syndrome (KRS), characterized by early-onset Parkinsonism with additional neurological features. KRS is caused by recessive loss-of-function mutations in the ATP13A2 gene encoding the endolysosomal ATPase ATP13A2. We show that loss of ATP13A2 causes a specific protein trafficking defect, and that Atp13a2 null mice develop age-related motor dysfunction that is preceded by neuropathological changes, including gliosis, accumulation of ubiquitinated protein aggregates, lipofuscinosis, and endolysosomal abnormalities. Contrary to predictions from in vitro data, in vivo mouse genetic studies demonstrate that these phenotypes are α-synuclein independent. Our findings indicate that endolysosomal dysfunction and abnormalities of α-synuclein homeostasis are not synonymous, even in the context of an endolysosomal genetic defect linked to Parkinsonism, and highlight the presence of α-synuclein-independent neurotoxicity consequent to endolysosomal dysfunction.
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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.