Dimitris P. Xirodimas 

Title

Targetting the Ubiquitin system for therapeutic intervention in Amyotrophic Lateral Sclerosis 

Abstract

Maintaining a functional and balanced proteome is a constant challenge for cells due to persistent proteotoxic stresses that cause protein damage. Misfolded and aberrant proteins have a tendency to aggregate, a process linked to various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS), as well as cancer and aging. To counteract aggregation, the protein quality control (PQC) network employs molecular chaperones for protein repair and refolding, while terminally damaged proteins are degraded via lysosomal and the Ubiquitin-proteasome pathways. Additionally, the spatial regulation of stress-induced protein aggregation in both the cytoplasm and nucleus plays a crucial role in maintaining proteostasis. 

I will discuss how the Ubiquitin-like protein NEDD8 is involved in the clearance of cytoplasmic protein-RNA condensates known as stress granules. Furthermore, I will highlight potential therapeutic strategies targeting components of the NEDD8 pathway for the treatment of ALS, based on the elimination of aberrant aggregates. 

Biography

I received my undergraduate degree in Molecular Biology in 1996 and obtained my PhD degree in Molecular Oncology in 2000 from the University of Dundee, Scotland, UK. I continued my postdoctoral studies in Prof. Sir David Lane’s laboratory in the same University before moving to Prof. Ronald T. Hay’s laboratory at the University of St. Andrews, Scotland, UK in 2004. In 2005, I was recipient of an AICR (Association for International Cancer Research) fellowship to develop an independent research team in the Centre for Gene Regulation and Expression at the University of Dundee. In 2011, I was recruited as Director of Research-Group leader in the Cell Biology Research Centre (CRBM), in Montpellier France. 

Our key objective is to understand how organisms deal with environmental stresses that cause protein damage (proteotoxic stress) and the mechanisms employed to maintain proteostasis. In particular, we aim to define how the so-called Protein Quality Control (PQC) system ensures the detection, repair and/or elimination of protein damage. We are focussing on the family of Ubiquitin and Ubiquitin-like molecules (Ubls), such as SUMO and NEDD8, which are critical regulatory components of the PQC system. We define their role in the degradation of misfolded proteins and on the formation of protein inclusions, which are regarded as hallmark in neurodegeneration. As the activity of enzymes within the Ubiquitin/Ubls pathways is often deregulated in pathologies including cancer and neurodegenerative disorders, we anticipate deciphering the role of the PQC system in the origin of such diseases.

Webpage: https://www.crbm.cnrs.fr/dimitris-xirodimas/?lang=en