SOD1A4V aggregation alters ubiquitin homeostasis in a cell model of ALS
Abstract
A hallmark of amyotrophic lateral sclerosis (ALS) pathology is the accumulation of ubiquitinated protein inclusions within motor neurons. Recent studies suggest the sequestration of ubiquitin (Ub) into inclusions reduces the availability of free Ub, which is essential for cellular function and survival. However, the dynamics of the Ub landscape in ALS have not yet been described. Here we show that Ub homeostasis is altered in a SOD1 cell model of ALS. Monitoring the distribution of Ub in SOD1-expressing cells, we show that Ub is present at the earliest stages of SOD1 aggregation and cells containing mutant SOD1 aggregates have greater ubiquitin-proteasome system (UPS) dysfunction. Furthermore, SOD1 aggregation is associated with the redistribution of Ub and depletion of the free Ub pool. Ubiquitomics analysis indicates that mutant SOD1 is associated with a shift of Ub to a pool of supersaturated proteins including those associated with oxidative phosphorylation and metabolism, corresponding with altered mitochondrial morphology and function. Taken together, these results suggest misfolded SOD1 contributes to UPS dysfunction and that Ub homeostasis is an important target for monitoring pathological changes in ALS.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2018
- Source ID
- 10.1242/jcs.209122
Entities
People
- Darren N Saunders
- Isabella Lambert-smith
- Jessie Mckenna
- Justin Yerbury
- Kara L. Vine
- Kristen Mitchell
- Luke Mcalary
- Natalie E. Farrawell
- Prajwal Ciryam
Organizations
- Australian Rotary Health
- Columbia University
- Illawarra Health & Medical Research Institute
- MND Australia
- National Health and Medical Research Council
- National Institutes of Health
- Northwestern University
- UK Fulbright Commission
- United States Department of Defense
- University of British Columbia
- University of Cambridge
- University of New South Wales
- University of Wollongong