Benjamin G Trist, Jennifer A Fifita, Alison Hogan, Natalie Grima, Bradley Smith, Claire Troakes, Caroline Vance, Christopher Shaw, Safa Al-Sarraj, Ian P Blair, Kay L Double. “Co-deposition of SOD1, TDP-43 and p62 proteinopathies in ALS: evidence for multifaceted pathways underlying neurodegeneration.” Acta Neuropath Comms

Multiple toxic proteins co-exist within nerve cells which are vulnerable to death in all major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Interactions between these proteins can speed up or slow down the rate of cell death in animal or cell models of ALS, suggesting these interactions may constitute targets for the development of therapies aiming to slow or halt nerve cell death in ALS patients. Despite mounting data examining these interactions in ALS-like disease models, there is comparatively little data describing whether these interactions are actually present in ALS patients. Further, studies examining these relationships seldom explore more than two proteins at a time. In this study, we investigated the co-deposition of SOD1, TDP-43 and p62 proteins in post-mortem spinal cord tissues from familial and sporadic ALS patients. We found that the amount and location of SOD1, TDP43 and p62 protein deposits within spinal cord nerve cells controlling movement varied significantly between familial and sporadic ALS patients. Our study is the first to profile spatial relationships between SOD1, TDP-43 and p62 protein deposits in spinal cord nerve cells of ALS patients, previously only studied in ALS disease models. Our findings suggest interactions between these three key ALS-linked proteins are likely to modulate the formation of their respective proteinopathies, and perhaps the rate of nerve cell degeneration, in ALS patients.