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/​d​i​m​i​t​r​i​s​-​x​i​r​o​d​i​m​a​s​/​?​l​a​n​g​=en