Ubiquitin Homeostasis Is Disrupted in TDP-43 and FUS Cell Models of ALS

• Published in: iScience 2020-11, Vol.23 (11), p.101700-101700, Article 101700
• Main Authors: Farrawell, Natalie E., McAlary, Luke, Lum, Jeremy S., Chisholm, Christen G., Warraich, Sadaf T., Blair, Ian P., Vine, Kara L., Saunders, Darren N., Yerbury, Justin J.
• Format: Article
• Language: English
• Subjects: Molecular Biology; Neuroscience; Protein Folding
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.101700

A major feature of amyotrophic lateral sclerosis (ALS) pathology is the accumulation of ubiquitin (Ub) into intracellular inclusions. This sequestration of Ub may reduce the availability of free Ub, disrupting Ub homeostasis and ultimately compromising cellular function and survival. We previously reported significant disturbance of Ub homeostasis in neuronal-like cells expressing mutant SOD1. Here, we show that Ub homeostasis is also perturbed in neuronal-like cells expressing either TDP-43 or FUS. The expression of mutant TDP-43 and mutant FUS led to UPS dysfunction, which was associated with a redistribution of Ub and depletion of the free Ub pool. Redistribution of Ub is also a feature of sporadic ALS, with an increase in Ub signal associated with inclusions and no compensatory increase in Ub expression. Together, these findings suggest that alterations to Ub homeostasis caused by the misfolding and aggregation of ALS-associated proteins play an important role in the pathogenesis of ALS. [Display omitted] •The expression of TDP-43M337V and FUSR495X causes UPS dysfunction in NSC-34 cells•The aggregation of TDP-43M337V and FUSR495X depletes the free Ub pool in cells•Ub homeostasis is altered in spinal cord tissue from patients with sALS•Perturbed Ub homeostasis is a common feature of ALS Molecular Biology; Neuroscience; Protein Folding