PD Guide

PARK9 (ATP13A2)

HSA9947, PARK9, KRPPD, ATP13A2, FLJ26510
Protein Degradation Pathways, Protein Trafficking

The PARK9 locus is associated with Kufor Rakeb disease, an autosomal recessive, juvenile onset parkinsonism (Williams et al., 2005). Mutations in the gene for ATP13A2, a P5-type ATPase, were subsequently identified in these cases as well as in some young onset forms of PD (Ramirez et al., 2006; Di Fonzo et al., 2007).

P-type ATPases generally maintain an ion gradient across the cell membrane, harnessing membrane potential to manufacture ATP, one of the staples of cellular energy. It is unclear how the loss-of-function mutations to ATP13A2 lead to PD pathogenesis, though interference with localization and lysosomal function may be affected (Gupta et al., 2008). ATP13A2 can protect against alpha-synuclein toxicity, suggesting a link between these two genetic pathways (Gitler et al., 2009).

Reference: 
Ramirez A, Heimbach A, Gründemann J, Stiller B, Hampshire D, Cid PL, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet. 2006;38(10):1184-91.
Williams DR, Hadeed A, al-Din A, Wreikat AL, Lees AJ. Kufor Rakeb disease: autosomal recessive, levodopa-responsive parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementia. Mov Disord. 2005;20(10):1264-71.
Di Fonzo A, Chien HF, Socal M, Giraudo S, Tassorelli C, Iliceto G, et al. ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease. Neurology. 2007;68(19):1557-62.
Gupta A, Dawson VL, Dawson TM. What causes cell death in Parkinson's disease? Ann Neurol. 2008;64 Suppl 2:S3-15.
Gitler AD, Chesi A, Geddie ML, Strathearn KE, Hamamichi S, Hill KJ, et al. Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat Genet. 2009;41(3):308-15.
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