The Greenamyre lab studies putative environment causes of Parkinson’s disease (PD) and developed the rotenone model of PD, which provided the first proof of the concept that systemic mitochondrial impairment could lead to selective nigrostriatal degeneration and α-synuclein (Lewy) pathology. Recent unpublished data show that trichloroethylene (TCE), an industrial solvent and prevalent groundwater contaminant implicated epidemiologically in PD risk, also causes selective nigrostriatal degeneration. Both rotenone and TCE induce endolysosomal dysfunction and pathological accumulation of pSer129-α-synuclein, apparently as a consequence of activating Leucine-Rich-Repeat Kinase 2 (LRRK2), mutation of which is the most common genetic cause of PD. LRRK2 kinase inhibitors protect against rotenone-induced endolysosomal impairment, prevent pSer129-α-synuclein accumulation and protect nigral dopamine neurons from degeneration. Thus, LRRK2 appears to play a central role in both genetic and environmental causes of PD.
