Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice

Significance The lack of a robust transgenic mouse model of loss of dopamine (DA) neurons has greatly hindered the study of Parkinson’s disease caused byLRRK2 mutations. In this manuscript, we report the development of catecholaminergic neuron-specific Tet-inducible conditional transgenic LRRK2 G2019S and LRRK2 G2019S kinase-dead transgenic mice, and show that LRRK2-induced DA and norepinephrine neurodegeneration is kinase-dependent and can occur in a cell-autonomous manner. Moreover, these models reveal that α-synuclein pathology is LRRK2 kinase-dependent and that there are LRRK2 kinase-dependent defects in clathrin-dependent endocytic trafficking that accompany mutant LRRK2-mediated neurodegeneration. These LRRK2 models have the potential to advance our understanding of mutant LRRK2-mediated degeneration of DA neurons.