Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures

Sequence variants at or near the leucine-rich repeat kinase 2 (LRRK2) locus have been associated with susceptibility to three human conditions: Parkinson disease (PD), Crohn’s disease and leprosy. Because all three disorders represent complex diseases with evidence of inflammation, we hypothesized a role for LRRK2 in immune cell functions

Cathepsin D expression level affects alpha-synuclein processing, aggregation, and toxicity <it>in vivo</it>

<p>Abstract</p> <p>Background</p> <p>Elevated <it>SNCA </it>gene expression and intracellular accumulation of the encoded α-synuclein (aSyn) protein are associated with the development of Parkinson disease (PD). To date, few enzymes have been examined for their ability to degrade aSyn. Here, we explore the effects of <it>CTSD </it>gene expression, which encodes the lysosomal protease cathepsin D (CathD), on aSyn processing.</p> <p>Results</p> <p>Over-expression of human <it>CTSD </it>cDNA in dopaminergic MES23.5 cell cultures induced the marked proteolysis of exogenously expressed aSyn proteins in a dose-dependent manner. Unexpectedly, brain extractions, Western blotting and ELISA quantification revealed evidence for reduced levels of soluble endogenous aSyn in <it>ctsd </it>knock-out mice. However, these CathD-deficient mice also contained elevated levels of insoluble, oligomeric aSyn species, as detected by formic acid extraction. In accordance, immunohistochemical studies of <it>ctsd</it>-mutant brain from mice, sheep and humans revealed selective synucleinopathy-like changes that varied slightly among the three species. These changes included intracellular aSyn accumulation and formation of ubiquitin-positive inclusions. Furthermore, using an established <it>Drosophila </it>model of human synucleinopathy, we observed markedly enhanced retinal toxicity in <it>ctsd</it>-null flies.</p> <p>Conclusion</p> <p>We conclude from these complementary investigations that: one, CathD can effectively degrade excess aSyn in dopaminergic cells; two, <it>ctsd </it>gene mutations result in a lysosomal storage disorder that includes microscopic and biochemical evidence of aSyn misprocessing; and three, CathD deficiency facilitates aSyn toxicity. We therefore postulate that CathD promotes 'synucleinase' activity, and that enhancing its function may lower aSyn concentrations <it>in vivo</it>.</p