A Role for Mitochondria-ER Crosstalk in Amyotrophic Lateral Sclerosis 8 Pathogenesis

Overview

Journal Life Sci Alliance

Date 2025 Jan 27

PMID 39870504

Authors

Cathal Wilson

Laura Giaquinto

Michele Santoro

Giuseppe Di Tullio

Valentina Morra

Wanda Kukulski

Rossella Venditti

Francesca Navone

Nica Borgese

Maria Antonietta De Matteis

Affiliations

Soon will be listed here.

Abstract

Protein 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.

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