Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase

Abstract

Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders. Although the complex molecular pathophysiology of neurodegeneration is largely unknown, major advances have been achieved by elucidating the genetic defects underlying mendelian forms of these diseases. This has led to the discovery of common pathophysiological pathways such as enhanced oxidative stress, protein misfolding and aggregation and dysfunction of the ubiquitin-proteasome system. Here, we describe loss-of-function mutations in a previously uncharacterized, predominantly neuronal P-type ATPase gene, ATP13A2, underlying an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia (PARK9, Kufor-Rakeb syndrome). Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. Our findings link a class of proteins with unknown function and substrate specificity to the protein networks implicated in neurodegeneration and parkinsonism.

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…Mutation screening of PD cases with early onset, but otherwise no atypical signs similar to Kufor-Rakeb syndrome, showed a few other mutations, both homozygous and heterozygous [246,247]. The ATP13A2 protein is a lysosomal ATPase [179], indicating that the lysosomal degradation pathway may play a role in the pathogenesis of PD.…”

“…To date (2010), 11 genes and an additional 3 genetic loci have been associated with PD [168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184]; two additional loci await to be confirmed [185,186]. The PD genes and loci are described in Table 4.…”

“…In 2006, mutations were identified in the ATP13A2 gene in a Jordanian and a Chilean family, one homozygous and one compound heterozygous [179]. A homozygous mutation was also identified in a Japanese patient with clinical features similar to Kufor-Rakeb syndrome but later onset [245].…”

A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

“…3b). Notably, mutations in ATP13A2 (PARK9) have been shown to cause Kufor-Rakeb syndrome, an autosomal recessive form of early onset parkinsonism and dementia [29]. Mutations in this gene cause a loss of function of the gene product, whereas expression of the normal gene is elevated in the substantia nigra of sporadic PD patients [30].…”

Young‐onset parkinsonism due to homozygous duplication of α‐synuclein in a consanguineous family

“…With a growing list of monogenetic causes of Parkinson's disease (PD),1–3 prioritization of genetic testing is made on the presumed mode of inheritance. In patients with early-onset PD from consanguineous families, the most common mode of inheritance is autosomal recessive.…”