Wilson, CathalCathalWilsonGiaquinto, LauraLauraGiaquintoSantoro, MicheleMicheleSantoroDi Tullio, GiuseppeGiuseppeDi TullioMorra, ValentinaValentinaMorraKukulski, WandaWandaKukulskiVenditti, RossellaRossellaVendittiNavone, FrancescaFrancescaNavoneBorgese, NicaNicaBorgeseDe Matteis, Maria AntoniettaMaria AntoniettaDe Matteis2025-03-062025-03-062025-04https://boris-portal.unibe.ch/handle/20.500.12422/204587Protein aggregates in motoneurons, a pathological hallmark of amyotrophic lateral sclerosis, have been suggested to play a key pathogenetic role. ALS8, characterized by ER-associated inclusions, is caused by a heterozygous mutation in VAPB, which acts at multiple membrane contact sites between the ER and almost all other organelles. The link between protein aggregation and cellular dysfunction is unclear. A yeast model, expressing human mutant and WT-VAPB under the control of the orthologous yeast promoter in haploid and diploid cells, was developed to mimic the disease situation. Inclusion formation was found to be a developmentally regulated process linked to mitochondrial damage that could be attenuated by reducing ER-mitochondrial contacts. The co-expression of the WT protein retarded P56S-VAPB inclusion formation. Importantly, we validated these results in mammalian motoneuron cells. Our findings indicate that (age-related) damage to mitochondria influences the propensity of the mutant VAPB to form aggregates via ER-mitochondrial contacts, initiating a series of events leading to disease progression.en500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & healtharticle10.48620/857953987050410.26508/lsa.202402907