Role and therapeutic potential of PLIN3 in neuromuscular diseases

Dr. Francesca Amati, University of Lausanne

Abstract (lay summary see below)

Due to their role in energy supply and reduction of oxidative stress, mitochondria are key organelles in maintaining functional neurons and myocytes. Mitochondria degradation, called mitophagy allows discarding damaged or old mitochondria, stimulates de novo biogenesis and thus maintains an optimal and efficient mitochondrial network through a constant turnover. The classical mitophagy cascade is initiated at the membrane of the targeted mitochondria by the recruitment and accumulation of specific proteins, such as PINK1 and PARKIN, and ends with the recruitment of the autophagosome machinery. Many actors of this mitophagic pathway have been implicated in neuromuscular diseases, such as Parkinson disease and Charcot-Marie-Tooth. 

Our lab has recently identified Perilipin 3 (PLIN3) as a new mitophagic player. This protein, known mostly in lipid droplet metabolism, may represent an alternative mitophagic pathway independent from PINK1/PARKIN. The overall goal of this project is the characterization of PLIN3 to understand its action on mitochondria and its impact in skeletal muscle. Further, we will explore PLIN3 potential implications in the physiopathology of specific neuromuscular diseases, such as Hereditary Spastic Paraplegia.

This project may open new therapeutic endeavors where a controlled and moderate mitophagy could promote mitochondrial quality and maintain an efficient network in patients with neuromuscular disorders associated to the accumulation of damaged mitochondria.

Lay summary

Pour fonctionner les cellules s’appuient sur un métabolisme performant et finement régulé. Les mitochondries représentent les usines capables de convertir sucres et graisses en énergie. Les anomalies génétiques et physiologiques affectant la mitochondrie convergent vers l’apparition de désordres neuromusculaires.

Notre laboratoire a récemment identifié une protéine susceptible de participer au renouvellement des mitochondries et au maintien d’une population efficace. Notre projet vise à comprendre la fonction exacte de cette protéine et à définir son implication physiologique et pathologique. Notre deuxième objectif est de mettre au point un peptide capable de mimer l’action de notre protéine. Cette molécule pourrait participer au maintien d’un pool optimal de mitochondries, et ainsi pallier à l’accumulation d’organelles endommagées décrite dans plusieurs pathologies neuromusculaires.