Pathogenic LRRK2 causes age-dependent and region-specific deficits in ciliation, innervation and viability of cholinergic neurons

Abstract

Pathogenic activating point mutations in the LRRK2 kinase cause autosomal-dominant familial Parkinso[n]s disease (PD). In cultured cells, mutant LRRK2 causes a deficit in de novo cilia formation and also impairs ciliary stability. In brain, previous studies have shown that in PD patients due to the G2019S-LRRK2 mutation as well as in middle-aged G2019S-LRRK2 knockin mice, striatal cholinergic interneurons show a deficit in primary cilia. Here, we show that cilia loss in G2019S-LRRK2 knockin mice is not limited to cholinergic striatal interneurons but common to cholinergic neurons across distinct brain nuclei. The lack of cilia in cholinergic forebrain neurons is accompanied by the accumulation of LRRK2-phosphorylated Rab12 GTPase and correlates with the presence of dystrophic cholinergic axons. Those deficits are already evident in young adult mutant LRRK2 mice. In contrast, the age-dependent loss of cilia in brainstem cholinergic neurons correlates with an age-dependent loss of cholinergic innervation derived from this brain area. Strikingly, we find cholinergic cell loss in mutant LRRK2 mice that is age-dependent, cell type-specific and disease-relevant. The age-dependent loss of a subset of cholinergic neurons mimics that observed in sporadic PD patients, highlighting the possibility that these particular neurons may require functional cilia for long-term cell survival.