Mutations in theATP13A2Gene and Parkinsonism: A Preliminary Review

Abstract

Parkinson’s disease (PD) is a major neurodegenerative disorder for which the etiology and pathogenesis remain as elusive as for Alzheimer's disease. PD appears to be caused by genetic and environmental factors, and pedigree and cohort studies have identified numerous susceptibility genes and loci related to PD. Autosomal recessive mutations in the genesParkin, Pink1, DJ-1, ATP13A2, PLA2G6, andFBXO7have been linked to PD susceptibility. Such mutations inATP13A2, also namedPARK9, were first identified in 2006 in a Chilean family and are associated with a juvenile-onset, levodopa-responsive type of Parkinsonism called Kufor-Rakeb syndrome (KRS). KRS involves pyramidal degeneration, supranuclear palsy, and cognitive impairment. Here we review current knowledge about theATP13A2gene, clinical characteristics of patients with PD-associatedATP13A2mutations, and models of how the ATP13A2 protein may help prevent neurodegeneration by inhibitingα-synuclein aggregation and supporting normal lysosomal and mitochondrial function. We also discuss anotherATP13A2mutation that is associated with the family of neurodegenerative disorders called neuronal ceroid lipofuscinoses (NCLs), and we propose a single pathway wherebyATP13A2mutations may contribute to NCLs and Parkinsonism. Finally, we highlight how studies of mutations in this gene may provide new insights into PD pathogenesis and identify potential therapeutic targets.