Neuropathology in an α-synuclein preformed fibril mouse model occurs independent of the Parkinson’s disease-linked lysosomal ATP13A2 protein

Abstract

AbstractLoss-of-function mutations in theATP13A2(PARK9) gene are implicated in early-onset autosomal recessive Parkinson’s disease (PD) and other neurodegenerative disorders.ATP13A2encodes a lysosomal transmembrane P5B-type ATPase that is highly expressed in brain and specifically within the substantia nigra. Recent studies have revealed its normal role as a lysosomal polyamine transporter, although its contribution to PD-related pathology remains unclear. Cellular studies report that ATP13A2 can regulate α-synuclein (α-syn) secretion via exosomes. However, the relationship between ATP13A2 and α-syn in animal models remains inconclusive.ATP13A2knockout (KO) mice exhibit lysosomal abnormalities and reactive astrogliosis but do not develop PD-related neuropathology. Studies manipulating α-syn levels in mice lacking ATP13A2 indicate minimal effects on pathology. The delivery of α-syn preformed fibrils (PFFs) into the mouse striatum is a well-defined model to study the development and spread of α-syn pathology. In this study, we unilaterally injected wild-type (WT) and homozygousATP13A2KO mice with mouse α-syn PFFs in the striatum and evaluated mice for neuropathology after 6 months. The distribution, extent and spread of α-syn aggregation in multiple regions of the mouse brain was largely independent of ATP13A2 expression. The loss of nigrostriatal pathway dopaminergic neurons and their nerve terminals induced by PFFs were equivalent in WT andATP13A2KO mice. Reactive astrogliosis was induced equivalently by α-syn PFFs in WT and KO mice but was significantly higher inATP13A2KO mice due to pre-existing gliosis. We did not identify asymmetric motor disturbances, microglial activation, or axonal damage induced by α-syn PFFs in WT or KO mice after 6 months. Although α-syn PFFs induce an increase in lysosomal number in the substantia nigra in general, TH-positive dopaminergic neurons did not exhibit either increased lysosomal area or intensity, regardless ofATP13A2genotype. Our study evaluating the spread of α-syn pathology reveals no exacerbation of α-syn pathology, neuronal loss, astrogliosis or motor deficits inATP13A2KO mice, suggesting that selective lysosomal abnormalities resulting from ATP13A2 loss do not play a major role in α-syn clearance or propagationin vivo.