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Most studies have focused on accumulation of neurotoxic \u03b1-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\u2013Rakeb syndrome (KRS), characterized by early-onset Parkinsonism with additional neurological features. KRS is caused by recessive loss-of-function mutations in the<jats:italic>ATP13A2<\/jats:italic>gene encoding the endolysosomal ATPase ATP13A2. We show that loss of ATP13A2 causes a specific protein trafficking defect, and that<jats:italic>Atp13a2<\/jats:italic>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<jats:italic>in vitro<\/jats:italic>data,<jats:italic>in vivo<\/jats:italic>mouse genetic studies demonstrate that these phenotypes are \u03b1-synuclein independent. Our findings indicate that endolysosomal dysfunction and abnormalities of \u03b1-synuclein homeostasis are not synonymous, even in the context of an endolysosomal genetic defect linked to Parkinsonism, and highlight the presence of \u03b1-synuclein-independent neurotoxicity consequent to endolysosomal dysfunction.<\/jats:p>","DOI":"10.1523\/jneurosci.0632-14.2015","type":"journal-article","created":{"date-parts":[[2015,4,8]],"date-time":"2015-04-08T16:35:34Z","timestamp":1428510934000},"page":"5724-5742","source":"Crossref","is-referenced-by-count":106,"title":["\u03b1-Synuclein-Independent Histopathological and Motor Deficits in Mice Lacking the Endolysosomal Parkinsonism Protein Atp13a2"],"prefix":"10.1523","volume":"35","author":[{"given":"Lauren 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