LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation

Abstract Parkinson’s disease is characterized by the progressive degeneration of dopaminergic neurons within substantia nigra pars compacta and presence protein aggregates in surviving neurons. The LRRK2 G2019S mutation one major determinants familial cases leads to late-onset with pleomorphic pathology, including α-synuclein accumulation deposition inclusions. We demonstrated that phosphorylates N-ethylmaleimide sensitive factor (NSF). observed containing NSF basal ganglia specimens from patients carrying variant, cellular animal models expressing variant. found kinase activity induces toxic aggregates. Of note, induction autophagy cleared aggregation rescued motor cognitive impairment aged hG2019S bacterial artificial chromosome (BAC) mice. suggest pathological phosphorylation impacts on biochemical properties, thus causing formation cytotoxic