Ramirez A et al. (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38: 1184–1191

The causal connection between specific genetic mutations and mendelian forms of neurodegenerative disease has been useful in determining the pathophysiological pathways underlying these disorders. In a recent study, Ramirez et al. described loss-of-function mutations in ATP13A2—a previously uncharacterized P-type ATPase gene—that cosegregate with Kufor–Rakeb syndrome (KRS), a form of early onset parkinsonism with pyramidal degeneration and dementia.

Linkage analysis and mutation screening of a large nonconsanguineous Chilean family with multiple cases of early onset parkinsonism identified a critical KRS interval of 6.6 cM containing around 40 genes. Two separate mutations in the ATP13A2 gene cosegregated with all incidences of KRS. The causative role of the gene was confirmed in the Jordanian family in which KRS was originally described; a homozygous 22-base-pair duplication was observed in all affected individuals.

Ramirez et al. showed that AT132 is predominantly expressed in the brain. The wild-type protein was found to colocalize with lysosomal membrane proteins, whereas the mutant protein accumulated in the endoplasmic reticulum and was degraded by the proteasome. Levels of mutant protein were notably lower than those of the wild-type protein. The authors suggest two pathophysiological mechanisms that could cause parkinsonism: first, an overload with mutant AT132 could cause toxic aggregation leading to proteasomal dysfunction; second, loss of ATP13A2 function could result in insufficient lysosomal protein degradation. Determining the function of ATP13A2 would contribute to our understanding of the protein networks implicated in neurodegenerative disorders.