Giovanni Piccoli

Tuesday, 30 October 2018 | 3:00 pm

Assistant Professor and Assistant TelethonScientist, Dulbecco Telethon Institute, Laboratory of Biology of Synapse, Center for Integrative Biology (CIBIO), University of Trento, ITALY

Overexpression of Parkinson’s disease-associated mutationLRRK2 G2019S in mouse induces behavioural deficits andprotein aggregation

(Host: O. Burrone)

Parkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta and the formation of protein aggregates in surviving neurons. LRRK2 G2019S mutation is 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 G2019S mouse model demonstrates an age- dependent motor and cognitive impairment. We observed the presence of aggregates containing N-ethylmaleimide sensitive factor (NSF) in basal ganglia specimen from G2019S carrier PD patients and in cellular and animal model expressing LRRK2 G2019S variant.

We found that LRRK2 G2019S kinase activity affects NSF degradation and induces its accumulation in toxic aggregates. Noteworthy, 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 substrates catabolism thus causing the formation of cytotoxic protein inclusions.