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 genes Parkin, Pink1, DJ-1, ATP13A2, PLA2G6, and FBXO7 have been linked to PD susceptibility. Such mutations in ATP13A2, also named PARK9, 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 the ATP13A2 gene, clinical characteristics of patients with PD-associated ATP13A2 mutations, and models of how the ATP13A2 protein may help prevent neurodegeneration by inhibiting α-synuclein aggregation and supporting normal lysosomal and mitochondrial function. We also discuss another ATP13A2 mutation that is associated with the family of neurodegenerative disorders called neuronal ceroid lipofuscinoses (NCLs), and we propose a single pathway whereby ATP13A2 mutations 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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder for which the etiology and pathogenesis remain elusive, it is known to be a multifactorial disease involving both genetic and environmental factors
Autosomal recessive mutations in six of these genes have been linked to the disease: Parkin (PARK2) [4], DJ-1 (PARK7) [5], PINK1 (PARK6) [6], ATP13A2 (PARK9) [7], PLA2G6 (PARK14) [8], and FBXO7 (PARK15) [9]
Studies with cultures of fibroblast cells and DA cells taken from PD patients with ATP13A2 mutations showed that inhibiting ATP13A2 function decreased the ability of lysosomes to degrade proteins and mediate clearance of autophagosomes [37]
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder for which the etiology and pathogenesis remain elusive, it is known to be a multifactorial disease involving both genetic and environmental factors. Autosomal recessive mutations in six of these genes have been linked to the disease: Parkin (PARK2) [4], DJ-1 (PARK7) [5], PINK1 (PARK6) [6], ATP13A2 (PARK9) [7], PLA2G6 (PARK14) [8], and FBXO7 (PARK15) [9]. Autosomal recessive mutations in the ATP13A2 gene were first discovered in 2006 in a single Chilean pedigree [7]. Subsequent studies in several other countries linked other mutations to KRS and early-onset Parkinsonism. ATP13A2 mutations have been associated with the occurrence of neurodegenerative disorders called neuronal ceroid lipofuscinoses (NCLs) in patients with Parkinsonism [10]. Some of the NCL-associated mutations overlap with PD-associated ones, suggesting a common pathway in the two types of neurological disease. These findings point to the gene and/or protein as a potential therapeutic target
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