Abstract
BackgroundATP13A2 (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.ResultsIn 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-1-11) contains supplementary material, which is available to authorized users.
Highlights
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
Increased Aβ42 levels in dementia with Lewy bodies (DLB) compared with PD cases Despite shorter disease durations for cases with DLB compared with PD (Table 1), Enzyme-linked immunosorbent assay (ELISA) results from the parahippocampal cortex show a 1.9-fold increase in relative membrane-associated Aβ42 in pure DLB over PD levels (p = 0.05), with a positive correlation between βamyloid 1–42 (Aβ42) and α-synuclein levels (R = 0.66, p = 0.05)
Similar changes were observed in the parahippocampal cortex, with increased levels of membrane-associated α-synuclein (280314 ± 44-49% increase from control levels, p = 0.018) and reduced levels of membrane-associated ATP13A2 (39-55 ± 8-10% reduction from control levels, p = 0.009) in PD and DLB cases compared with controls (Figure 1B)
Summary
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. We sought to assess if ATP13A2 levels in Lewy body disease are modified by Alzheimer-type βamyloid deposition by evaluating cases of pure PD that lack β-amyloid-positive plaques and pure dementia with Lewy bodies (DLB) and β-amyloid-positive plaques. Such cases were examined for changes in and correlations between ATP13A2, α-synuclein and β-amyloid protein levels in cortical regions with and without Lewy bodies using Western blotting and ELISA. To assess the earliest changes associated with α-synuclein aggregation, we evaluated regions displaying α-synuclein that do not undergo major neuron loss in PD
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