LRRK2 and Parkinson disease: PD-associated autosomal dominant mutations in LRRK2 have generally been hypothesized to induce pathology through a gain-of-function mechanism, based in part on the observation that a subset of these clinical mutations in LRRK2 lead to increased kinase activity in vitro towards generic kinase substrates, as well as to increased LRRK2 autophosphorylation in vitro and in vivo16, 44, 45.