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A perturbed network in neurodegeneration

Description Three proteins act in concert to cause neuronal pathology Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that share clinical, pathological, and genetic features. A pathological hallmark of ALS-FTD is the presence of ubiquitin-positive protein aggregates (or inclusions) in the cytoplasm of affected neurons. The main component of inclusions in most ALS cases and half of FTD cases is the mostly nuclear RNA binding protein, TDP-43 (TAR DNA binding protein 43) (1). The existence of rare ALS-causing mutations in TARDBP, which encodes TDP-43, suggests a causal role of TDP-43 dysfunction in the pathogenesis of ALS-FTD (2, 3). Pathogenic mutations in several other genes are more common in ALS and FTD, but how they trigger cytoplasmic aggregation of TDP-43 remains unknown. On page 94 of this issue, Shao et al. (4) partly address this by showing that two ALS-FTD–associated genes cooperate to cause TDP-43 cytoplasmic aggregation by impairing endosome maturation.