Cell-autonomous role of leucine-rich repeat kinase in the protection of dopaminergic neuron survival.

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease (PD). However, whether LRRK2 mutations cause PD and degeneration of dopaminergic (DA) neurons via a toxic gain-of-function or a loss-of-function mechanism is unresolved and has pivotal implications for LRRK2-based PD therapies. In this study, we investigate whether <i>Lrrk2</i> and its functional homolog <i>Lrrk1</i> play a cell-intrinsic role in DA neuron survival through the development of DA neuron-specific <i>Lrrk</i> conditional double knockout (cDKO) mice. Unlike <i>Lrrk</i> germline DKO mice, DA neuron-restricted <i>Lrrk</i> cDKO mice exhibit normal mortality but develop age-dependent loss of DA neurons, as shown by the progressive reduction of DA neurons in the substantia nigra pars compacta (SNpc) at the ages of 20 and 24 months. Moreover, DA neurodegeneration is accompanied with increases in apoptosis and elevated microgliosis in the SNpc as well as decreases in DA terminals in the striatum, and is preceded by impaired motor coordination. Taken together, these findings provide the unequivocal evidence for the cell-intrinsic requirement of LRRK in DA neurons and raise the possibility that LRRK2 mutations may impair its protection of DA neurons, leading to DA neurodegeneration in PD.