LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation

Parkinsons disease (PD) is characterized by the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta and the presence of protein aggregates in surviving neurons. LRRK2 G2019S mutation is one the major determinant of familial PD cases and leads to late-onset PD with pleomorphic pathology, including alpha-synuclein accumulation and deposition of protein inclusions. LRRK2 binds and phosphorylates N-ethylmaleimide sensitive factor (NSF). We observed aggregates containing NSF in basal ganglia specimens from G2019S carrier PD patients and in cellular and animal models expressing the LRRK2 G2019S variant. We found that LRRK2 G2019S kinase activity induces the accumulation of NSF in toxic aggregates. Noteworthy, the induction of autophagy cleared NSF aggregation and rescued motor and cognitive impairment observed in aged hG2019S BAC mice. We suggest that LRRK2 G2019S pathological phosphorylation hampers substrate catabolism, thus causing the formation of cytotoxic protein inclusions. HighlightsO_LILRRK2 phosphorylates NSF in vivo C_LIO_LINSF aggregates in complementary LRRK2 G2019S models C_LIO_LILRRK2 G2019S kinase activity induces NSF accumulation in toxic aggregates C_LIO_LIAutophagy induction rescues hG2019S BAC mice motor and cognitive impairment C_LI