LRRK2 modifies α-syn pathology and spread in mouse models and human neurons.

摘要: Progressive aggregation of the protein alpha-synuclein (α-syn) and loss dopaminergic neurons in substantia nigra pars compacta (SNpc) are key histopathological hallmarks Parkinson's disease (PD). Accruing evidence suggests that α-syn pathology can propagate through neuronal circuits brain, contributing to progressive nature disease. Thus, it is therapeutically pertinent identify modifiers transmission as potential targets slow down progression. A growing number genetic mutations risk factors has been identified studies familial sporadic forms PD. However, how these genes affect pathological transmission, whether they be targeted for therapeutic interventions, remains unclear. We performed a screen associated with PD parkinsonism aggregation, using an preformed-fibril (PFF) induction assay. found decreased expression Lrrk2 Gba modulated mouse primary neurons. Conversely, increased from mice expressing PD-linked LRRK2 G2019S mutation. In vivo, transgenic mice, we observed acceleration degeneration SNpc, exacerbated degeneration-associated neuroinflammation behavioral deficits. To validate our findings human context, established novel model induced pluripotent stem cell (iPS)-derived (iNs), where PFFs triggered endogenous time-dependent manner. subject-derived iNs, mutation enhanced whereas aggregation. Collectively, establish strong interaction between gene across models. Since clinical trials inhibitors currently underway, raise possibility may effective broadly, beyond cases caused by mutations.