ClulnhForPD PROJECT

FRRB Project 1737591 - Exploring LRRK2-Clusterin pathway as a therapeutic strategy for Parkinson’s disease

PROJECT SUMMARY

Parkinson's disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons and the formation of α-synuclein protein inclusions in surviving neurons. The disease is thought to be caused by cell propagation of α-synuclein aggregates released from damaged and degenerated neurons. Therefore, the degradation of these aggregates is a key process to control the progression of the disease.

Preliminary results generated in our laboratory showed that the protein Clusterin is able to bind α-synuclein aggregates and thus interfering with their phagocytosis and degradation by astrocytes. Furthermore, we observed that astrocytes lacking Lrrk2 gene, a gene related to familial and sporadic Parkinson's cases, exhibited reduced Clusterin levels. These results led us to hypothesize that one of the underlying pathological mechanisms of the disease could be the de-regulation of the LRRK2-Clusterin cellular process which could favor the neuronal propagation of α-synuclein aggregates and thus the progression of the disease. Therefore, this research project has as main objective the investigation of the cellular process LRRK2-Clusterin as a cause of the propagation of pathological α-synuclein aggregates and of the neurodegeneration observed in PD. Interestingly, this project will allow us to investigate the pharmacological inhibition of the LRRK2-Clusterin cellular pathway (with LRRK2 kinase inhibitors) as a therapeutic strategy for PD.

In these two years of research, we identified the mechanism by which LRRK2 regulates Clusterin levels. Furthermore, we found that both murine and human astrocytes carrying LRRK2 G2019S mutation exhibit defects in the phagocytosis of α-synuclein aggregates, which dysfunction causes increased propagation of α-synuclein aggregates in neurons.