Data di Pubblicazione:
2023
Citazione:
Molecular pathways controlling unconventional non-AUG translated proteins levels in ALS / R. Cristofani. ((Intervento presentato al 20. convegno National Congress of the Italian Society for Neuroscience tenutosi a Torino nel 2023.
Abstract:
Intronic GGGGCC (G4C2) hexanucleotide repeat expansions within the human C9orf72 gene represents the most common cause of familial and sporadic forms of amyotrophic lateral sclerosis (fALS) and frontotemporal dementia (FTD). Repeat-associated non-AUG (RAN) translation of resulting RNA leads to the production of neurotoxic dipeptide-repeat (DPR) proteins. DPR proteins aggregate into cytoplasm or nuclei of motor neurons, altering the proteotoxic response machinery. The protein quality control (PQC) system maintains protein homeostasis by re-folding (by chaperone) or by degradation (by autophagy or proteasome) of misfolded proteins to counteract proteotoxic events. We identified i) forskolin (FSK, a cAMP-elevating compounds) as DPR protein levels enhancer, and ii) geldanamycin (GELD, an HSP90 inhibitor) and spironolactone (SPL, an aldosterone antagonist), as reducer of DPR protein levels. Interestingly, FSK-increased cAMP levels may activate PKA. We demonstrated that PKA blockage (by H89 treatment) or knockdown reduced translation efficiency (polyribosome profile) of DPRs in neuronal cells overexpressing DPR proteins, and in C9ALS/FTD patient-derived iPSC motor neurons with endogenous DPR protein levels. In neurons, we analysed the involvement of the two main degradative pathways. We demonstrated that proteasome and autophagy pathways are responsible for proteins degradation in cells treated with GELD and with SPL suggesting that the degradative systems and the selective modulation of RAN translation can be molecular targets to reduce toxic protein levels and neurotoxicity in REND.
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Elenco autori:
R. Cristofani
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