Venue: Centre Broca
Pr Dmitry Lim
Associate Professor,
Department of Pharmaceutical Sciences, Università del Piemonte Orientale
Novara, Italy
https://research.uniupo.it/en/persons/dmitry-lim-11/
Invited by Giulia Dematteis and Giovanni Marsicano (Neurocentre Magendie)
Title
A chicken and the egg: ER-mitochondria interaction and protein homeostasis in Alzheimer’s disease and beyond.
Abstract
Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), are characterised by early dysregulation of protein-synthetic and proteolytic mechanisms leading to accumulation of misfolded or aggregation-prone proteins. Protein dyshomeostasis in astroglial cells, homeostatic cells in the CNS, leads to loss of their neuroprotective functions, predisposing neurons to dysfunction and degeneration.
Mitochondria-ER contact sites (MERCS) emerged as morpho-functional hubs coordinating core cellular functions, including protein synthesis and degradation. Although growing body of reports associate disruption of MERCS with NDDs and AD pathogenesis, promoting MERCS as therapeutic target, their primary role in cell dysfunctions remain controversial. We reported that, in astrocytes, dysregulation of protein synthesis and degradation, characteristic for AD astrocytes, may be mimicked by artificial shortening of ER-mitochondrial distance to ~10nm. Contrarily, stabilization of MERCS at near physiological distance of ~20nm in 3xTg-AD astrocytes, rescued not only mitochondrial Ca2+ uptake, but also protein homeostasis including normalization of autophagic flux and proteasomal activity. Strikingly, AD-relevant pathological conversion of constitutive proteasome to immunoproteasome was also rescued.
In another pathological context, we and others found that disruption of MERCS represent the earliest event of high-fat diet-induced obesity. Moreover, reports suggest that stabilization MERCS at about 20nm in liver cells prevented a diet-induced obesity and insulin resistance in mice. Altogether, our and other’s data suggest that MERCS alterations represent an earliest and causative event unleashing downstream disruption of protein homeosis. These results also prove that MERCS represent a druggable target for development of therapeutic strategies.