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

Abstract

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, α-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 α-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.

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

“…2013) and recently in Atp13a2‐deficient (CLN12) mice (Schultheis et al. 2013). α ‐Synuclein is known to modulate synaptic pathology in mice, at least in part through interactions with another synaptic protein, CSP‐ α (Chandra et al.…”

ATP13A2/PARK9 Regulates Secretion of Exosomes and α-Synuclein

“…In addition, PARK9 expression levels were increased in postmortem brains from sporadic PD patients (Ramirez et al, 2006;Ramonet et al, 2012). Studies in cultured neurons also demonstrated that transiently expressed wild-type PARK9 localized to acidic vesicles (Ramirez et al, 2006;Tan et al, 2011;Ramonet et al, 2012). We and others have shown that depletion of PARK9 causes lysosomal dysfunction, accumulation of ␣-syn (Dehay et al, 2012;Usenovic et al, 2012a), and increased sensitivity to zinc .…”

“…Initial studies revealed that overexpression of PARK9 reduced the toxicity of ␣-synuclein (␣-syn) in yeast cells and rat primary dopaminergic neurons (Gitler et al, 2009). In addition, PARK9 expression levels were increased in postmortem brains from sporadic PD patients (Ramirez et al, 2006;Ramonet et al, 2012). Studies in cultured neurons also demonstrated that transiently expressed wild-type PARK9 localized to acidic vesicles (Ramirez et al, 2006;Tan et al, 2011;Ramonet et al, 2012).…”

“…Loss-of-function mutations in ATP13A2/PARK9 cause KuforRakeb syndrome (KRS), a rare autosomal recessive disorder characterized by early onset parkinsonism and other neurological symptoms, such as dementia and pyramidal signs (Najim al-Din et al, 1994;Ramirez et al, 2006). PARK9 belongs to P-type ATPase super family to which no specific substrates have been assigned (Axelsen and Palmgren, 1998).…”

“…PARK9 belongs to P-type ATPase super family to which no specific substrates have been assigned (Axelsen and Palmgren, 1998). PARK9 is expressed predominantly in CNS, especially in dopaminergic neurons of substantia nigra (Ramirez et al, 2006). Initial studies revealed that overexpression of PARK9 reduced the toxicity of ␣-synuclein (␣-syn) in yeast cells and rat primary dopaminergic neurons (Gitler et al, 2009).…”