Function and dysfunction of the  Parkinson's disease associated protein LRRK2 at the presynaptic site

Venue: Edificio Povo 2, via Sommarive nr. 9, Povo (Tn) - Room B101
 at 2:00 p.m.

• Giovanni Piccoli -  Università Vita e Salute, San Raffaele, Milano

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. G2019S mutation increases LRRK2 kinase activity and is toxic in vitro and in vivo.  However despite its relevance in PD, the physiological function of LRRK2 and the neurobiological impact of such kinase-enhancing mutation are far from being understood. In particular, few LRRK2 substrates have been validated up to now. Our data suggest that LRRK2 interacts with and phosphorylates  N-ethylmaleimide sensitive factor (NSF). LRRK2 phosphorylation influences NSF enzymatic activity and correlates with an increased synaptic vesicle turnover. Furthermore, although alpha-synuclein is their major component, Lewy bodies and the related inclusion body contain several proteins, including NSF. Interestingly, we observed the presence of alpha synuclein positive Lewy bodies containing NSF within the substantia nigra  from  G2019S carrier PD patients.  We  demonstrated in vitro and ex vivo that  LRRK2 G2019S phosphorylation impairs NSF ubiquitination and consequent degradation via proteasome thus inducing its accumulation in toxic aggregates. Finally, induction of autophagy ameliorates NSF deposition  in aged hG2019S BAC mice and prevent NSF associated toxicity.  We suggest that LRRK2  G2019S pathological phosphorylation alters substrates ubiquitination thus causing the formation of cytotoxic protein inclusions.