Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited α-synuclein accumulation and age-dependent sensorimotor deficits

Patrick J. Schultheis*, Sheila M. Fleming, Amy K. Clippinger, Jada Lewis, Taiji Tsunemi, Benoit Giasson, Dennis W. Dickson, Joseph R. Mazzulli, Mark E. Bardgett, Kristi L. Haik, Osunde Ekhator, Anil Kumar Chava, John Howard, Matt Gannon, Elizabeth Hoffman, Yinhuai Chen, Vikram Prasad, Stephen C. Linn, Rafael J. Tamargo, Wendy WestbroekEllen Sidransky, Dimitri Krainc, Gary E. Shull

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

114 Scopus citations


Mutations in ATP13A2 (PARK9), encoding a lysosomal P-type ATPase, are associated with both Kufor-Rakeb syndrome (KRS) and neuronal ceroid lipofuscinosis (NCL). KRS has recently been classified as a rare genetic form of Parkinson's disease (PD), whereas NCL is a lysosomal storage disorder. Although the transport activity of ATP13A2 has not been defined, in vitro studies show that its loss compromises lysosomal function, which in turn is thought to cause neuronal degeneration. To understand the role of ATP13A2 dysfunction in disease, we disrupted its gene in mice. Atp13a2-/- and Atp13a2+/+ mice were tested behaviorally to assess sensorimotor and cognitive function at multiple ages. In the brain, lipofuscin accumulation, a-synuclein aggregation and dopaminergic pathology were measured. Behaviorally, Atp13a2-/- mice displayed late-onset sensorimotor deficits. Accelerated deposition of autofluorescent storage material (lipofuscin) was observed in the cerebellum and in neurons of the hippocampus and the cortex of Atp13a2-/- mice. Immunoblot analysis showed increased insoluble a-synuclein in the hippocampus, but not in the cortex or cerebellum. There was no change in the number of dopaminergic neurons in the substantia nigra or in striatal dopamine levels in aged Atp13a2-/- mice. These results show that the loss of Atp13a2 causes sensorimotor impairments, α-synuclein accumulation as occurs in PD and related synucleinopathies, and accumulation of lipofuscin deposits characteristic of NCL, thus providing the first direct demonstration that null mutations in Atp13a2 can cause pathological features of both diseases in the same organism.

Original languageEnglish (US)
Article numberddt057
Pages (from-to)2067-2082
Number of pages16
JournalHuman molecular genetics
Issue number10
StatePublished - May 2013

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Molecular Biology


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