INSERM U1242 Oncogenesis Stress Signaling - SPECIAL SEMINAR - Centre De Lutte Contre Le Cancer Eugène Marquis

Mechanisms of Unconventional Protein Secretion – from basic research to neurodegenerative disease therapeutics

Dr. Julien VILLENEUVE

CRCN at CNRS

Institute of Functional Genomics (IGF) - MONTPELLIER

Abstract

Alzheimer's and Parkinson's diseases are neurodegenerative diseases (NDs), characterized by the accumulation of misfolded and aggregated proteins such as Tau and alpha-synuclein (aSNC) in the central nervous system. These pathogenic proteins can spread from cell to cell, and this intercellular propagation contributes to the disease progression. Therefore, uncovering the molecular and cellular mechanisms underlying the intercellular transmission of Tau and aSNC is of utmost importance.
Recently, we demonstrated that lysosomes can play a critical role in the unconventional secretion of Tau and aSNC through lysosomal exocytosis. Thus, a critical challenge now is to understand what makes lysosomes a transport carrier and secretory compartment, promoting Tau and αSNC dissemination.
Toward this objective, we are dissecting the molecular determinants required to divert lysosomes toward compartments competent for fusion with the plasma membrane, and to identify factors involved at every step of Tau and αSNC trafficking. For this, functional assays on lysosomes, pooled genome-wide CRISPR screens, and proteomic approaches are used. Second, we are investigating the role of identified factors in iPSC-derived neurons and zebrafish and drosophila models to validate their pathological relevance and reveal their therapeutic potential. Finally, we are testing the role of lysosomes as the main sorting station in ND patients by assessing the levels of lysosomal enzymes in cerebrospinal fluid (CSF) of patients.
Overall, our work may lead to the identification of novel therapeutic targets and diagnostic markers, paving the way for innovative strategies to prevent or slow the progression of NDs.