Progetto Cariplo

  • Fondazione Cariplo - Bando 2011 RICERCA SCIENTIFICA IN AMBITO BIOMEDICO
  • LRRK2 as a therapeutic target in Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative disease clinically characterized by bradykinesia, rigidity and resting tremor. Recent studies have enlightened that synaptic dysfunction, implicated in numerous studies of animal models of PD, is both a key factor in PD and an early stage marker in presymptomatic patients. Although the majority of cases are sporadic, mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene (PARK8; OMIM 609007) are linked to late-onset autosomal dominant Parkinson’s disease. Mutations in LRRK2 account for up to 13% of familial PD cases compatible with dominant inheritance and 1 to 2% of sporadic PD patients, thus suggesting this protein as the most significant player in PD pathogenesis identified to date. The LRRK2 protein has a molecular weight of approximately 280 kDa and contains several domains including a kinase domain. Robust literature suggests that the pathological mutations bring to an increase of LRRK2 kinase activity. Despite its predominance in PD, the physiological function of LRRK2 is not known and also its precise role in the aetiology of PD is far from being understood. Strikingly, neurotransmission defects have been repeatedly observed in different LRRK2 models. Accordingly, we have recently shown that electrophysiological properties as well as vesicular trafficking in the presynaptic pool depend on the presence of LRRK2 as an integral part of presynaptic protein complex. Given the presynaptic alteration seen in LRRK2 disease model, an attractive hypothesis is that LRRK2 influences synaptic structure and function through effects on presynaptic proteins. One possibility is that mutated LRRK2 alters synaptic vesicles (SV) trafficking via impaired phosphorylation of presynaptic proteins. Our major aim is to identify and understand the molecular basis behind PD onset and progression. Thus we aim to uncover if presynaptic proteins critical for SV trafficking are target of the pathological kinase activity of LRRK2 and how this mechanism influences proper synaptic function. Finally, given that inhibitors of LRRK2 kinase activity have been recently characterized, we propose to evaluate their effect on subtle neuron functions in different LRRK2 PD in vitro models. The pharmacological inhibition of LRRK2 kinase activity is in fact a promising therapeutic modality for the treatment of neurodegeneration in PD, but its real potential and eventual side effect have to be deeply evaluated. In order to move the first step towards the targeting of LRRK2 kinase activity as a therapeutic strategy, we will evaluate the effect of LRRK2 kinase inhibitor in terms of capability to rescue functional phenotype. In order to gain more physiological information, we will test selected candidates on a high complexity model specifically developed for this project: dopaminergic neurons derived from LRRK2 patients. In fact, patient derived iPS cells constitute the best tool to gain information about a multi-factor disease as PD where genomic background has a deep effect on age of onset and clinical phenotype. We expect that these studies will provide a framework to identify what the direct biochemical and physiological consequences of LRRK2 mutations are, providing a better understanding of LRRK2 function and, potentially, new molecular handle to design the diagnosis and the treatment of the disease.

National coordinator

  • Dott. Giovanni Piccoli - Istituto di Neuroscienze CNR

Partner 3 scientific responsible

Partnership

  • l'Istituto di Neuroscienze CNR, Coordinator;
  • l'Università degli Studi di Milano, Dipartimento di Farmacologia, Chemioterpia e Tossicologia medica, “Partner 1”;
  • l'Università degli Studi di Padova, Dipartimento di Biologia , “Partner 2”;
  • l'Università degli Studi di Genova, Dipartimento di Medicina Sperimentale (DIMES) , “Partner 3”

Keywords

Parkinson’s disease, Leucine-rich repeat kinase 2, kinase inhibitors, disease modifying therapies