Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease comprising clinically indistinguishable sporadic (s) and familial (f) forms, associated with an aberrant behavior of a number of gene products (SOD1, TDP-43, FUS, UBQLN2, VCP, FIG4, CHMP2B, SQSTM1, C9orf72). Most of these proteins are involved in protein degradation via the ubiquitin proteasome (UPP) or the autophagolysosomal (APLP) pathways, as well as in RNA processing or stress granule (SG) response. In ALS, motoneurons accumulate protein aggregates that contain RNA-binding proteins markers of SGs. Thus, proteostasis (mediated by the protein quality control, PQC) and ribostasis (involving SGs) may be interconnected and their imbalance may participate to ALS. At present, it is largely unknown whether interplay between PQC (chaperones, UPP and APLP) and SG dynamics exists and to what extent deregulated PQC may affect SGs, thereby contributing to ALS. Notably, valosin containing protein (VCP) assists with autophagy SG clearance (1) and we found that inhibition of autophagy, lysosomes and depletion of VCP alter SG size, number and composition, pointing to APLP and chaperone-assisted degradation as interconnected processes. These data imply that imbalances in proteostasis and deregulated APLP, which occur in ALS, will affect SG morphology and composition; thus, defective SG response may also contribute to ALS. Here, we will: 1) dissect how interplay between PQC, VCP and SGs occurs, identifying new players involved in this process and specific clients whose VCP-assisted/APLP-mediated degradation affects SGs; 2) identify the functional consequences of impaired SG response; 3) test whether boosting chaperone-assisted degradation or client targeting may rescue SG morphology and composition. Using motoneuronal ALS cell models we will characterize the impact of ALS mutants of VCP on SG and proteostasis. In parallel, we will characterize and compare SG morphology and composition in fibroblasts and lymphoblasts derived from ALS patients with mutations in VCP, TDP-43, FUS, SOD1 and C9orf72, as well as in motoneurons derived from ALS-iPSCs. Our approach will provide mechanistic insight on the interplay between VCP, PQC and SGs. It will also demonstrate whether/how SG composition and dynamics are affected in ALS and how this correlates with proteostasis alterations, representing a common pathogenic mechanism; finally, our data will provide the molecular basis for the design of new therapeutic strategy.
|Data di pubblicazione:||2015|
|Titolo:||VCP AND AUTOPHAGOLYSOSOMAL PATHWAY: GUARDIANS OF PROTEOSTASIS AND STRESS GRANULE DYNAMICS. UNRAVELING THEIR IMPLICATIONS IN ALS|
|Autore/i:||Ganassi, M; Bigi, I; Seguin, Sj; Morelli, Ff; Mandrioli, J; Cereda, C; Poletti, A; Carra, S|
|Nome del convegno:||1 Simposio nazionale sulla SLA|
|Data del convegno:||12-14 novembre 2015|
|Luogo del convegno:||Napoli, Italia|
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