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α-Synuclein-independent histopathological and motor deficits in mice lacking the endolysosomal Parkinsonism protein Atp13a2.

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.

Pubmed ID: 25855184 RIS Download

Mesh terms: Adenosine Triphosphatases | Animals | Brain | Cytosol | Disease Models, Animal | Dopaminergic Neurons | Endosomes | Exploratory Behavior | Hindlimb Suspension | Hydrogen-Ion Concentration | Lipids | Lysosomes | Male | Membrane Proteins | Mice | Mice, Inbred C57BL | Mice, Knockout | Motor Activity | Nerve Tissue Proteins | Parkinsonian Disorders | Postural Balance | alpha-Synuclein

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Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS061098
  • Agency: NINDS NIH HHS, Id: P50 NS038370
  • Agency: NINDS NIH HHS, Id: NS038370
  • Agency: NINDS NIH HHS, Id: F31 NS078817
  • Agency: NIGMS NIH HHS, Id: T32 GM007863
  • Agency: NIA NIH HHS, Id: P30 AG038072
  • Agency: NINDS NIH HHS, Id: P50 NS091856
  • Agency: NCI NIH HHS, Id: P30 CA013330
  • Agency: NINDS NIH HHS, Id: R01 NS056049
  • Agency: NIA NIH HHS, Id: P01 AG031782

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