α-synuclein-independent histopathological and motor deficits in mice lacking the endolysosomal parkinsonism protein Atp13a2

Lauren R. Kett, Barbara Stiller, Megan M. Bernath, Inmaculada Tasset, Javier Blesa, Vernice Jackson-Lewis, Robin B. Chan, Bowen Zhou, Gilbert Di Paolo, Serge Przedborski, Ana Maria Cuervo, William T. Dauer

Research output: Contribution to journalArticle

47 Scopus citations

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-synucleinindependent neurotoxicity consequent to endolysosomal dysfunction.

Original languageEnglish (US)
Pages (from-to)5724-5742
Number of pages19
JournalJournal of Neuroscience
Volume35
Issue number14
DOIs
StatePublished - Apr 8 2015

Keywords

  • ATP13A2
  • Autophagy
  • Endolysosomal system
  • Genetics
  • Parkinson’s disease

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    Kett, L. R., Stiller, B., Bernath, M. M., Tasset, I., Blesa, J., Jackson-Lewis, V., Chan, R. B., Zhou, B., Di Paolo, G., Przedborski, S., Cuervo, A. M., & Dauer, W. T. (2015). α-synuclein-independent histopathological and motor deficits in mice lacking the endolysosomal parkinsonism protein Atp13a2. Journal of Neuroscience, 35(14), 5724-5742. https://doi.org/10.1523/JNEUROSCI.0632-14.2015