title: ATP13A2 (PARK9) protein levels are reduced in brain tissue of cases with Lewy bodies.
abstract: BACKGROUND
  ATP13A2 (PARK9) loss of function mutations are a genetic cause of an early-onset form of Parkinson's disease (PD), with in vitro studies showing that ATP13A2 deficits lead to lysosomal and mitochondrial dysfunction and α-synuclein accumulation, while elevated ATP13A2 expression reduces α-synuclein toxicity. The three human brain tissue studies assessing changes in ATP13A2 expression in PD produced divergent results; mRNA is increased while protein levels were observed to be either increased or decreased. This apparent conflict in protein levels might have arisen from examining Lewy body disease cases with coexisting Alzheimer-type pathologies.To assess whether ATP13A2 levels in Lewy body disease are modified by Alzheimer-type β-amyloid deposition, we evaluated cases of pure PD and pure dementia with Lewy bodies (DLB) for changes in ATP13A2, α-synuclein and β-amyloid protein levels in cortical regions with and without Lewy bodies.
  
  
  RESULTS
  In all Lewy body disease cases, we identified decreased ATP13A2 protein levels that correlated with increases in both α-synuclein and β-amyloid. Partial colocalization was observed between ATP13A2 and α-synuclein in Lewy bodies, whereas ATP13A2 did not colocalize with pathological β-amyloid deposition.
  
  
  CONCLUSIONS
  Our data show that patients with Lewy body diseases have an overall deficit in ATP13A2 protein levels, with the remaining protein being more insoluble and partially redistributing towards Lewy bodies. This supports the concept that increasing ATP13A2 levels may offer potential therapeutic benefits to patients with Lewy body diseases.
authors.affiliation: Neuroscience Research Australia, Sydney 2031, Australia. g.halliday@neura.edu.au.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Murphy
authors.forename: Louise
authors.initials: L
authors.lastname: Cottle
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Gysbers
authors.forename: Antony A
authors.initials: AA
authors.lastname: Cooper
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000378:metabolism*; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D020961:Lewy Body Disease / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: C514983:ATP13A2 protein, human; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C497604:SNCA protein, human; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); D006180:Proton-Translocating ATPases