STMN2 Regulation in Health, Stress and Disease

Amyotrophic Lateral Sclerosis (ALS) is one of the most aggressive neurodegenerative diseases, fatal within 2-5 years of symptom onset. Understanding the mechanisms underpinning disease development is key to the progression of therapeutic strategies. Over 97% of ALS patients possess TDP-43 proteinopathy, the mislocalisation and aggregation of the essential DNA/RNA binding protein TDP-43.
TDP-43 is a stress responsive protein capable of liquid-liquid phase separation; therefore, the response of TDP-43 to cellular stress was first investigated, having found its loss of function (LoF) phenotype under stress conditions. In order to characterise the downstream effects of this phenotype, I analysed splicing targets regulated by TDP-43 – primarily focusing on STMN2. A significant contributor to neuronal death in ALS pathogenesis is axonal degeneration, and STMN2 is an essential protein for the maintenance of axonal outgrowth and function via sustaining microtubule dynamics. Therefore, STMN2 is a target of significant interest in both mechanistic and translational research.
I further identified additional mechanisms of STMN2 depletion in the cellular stress response, not dependent on TDP-43 LoF, suggesting its downregulation may be a normal response to cellular stress. Perturbations to this process by ALS-associated mutations or other related mechanisms may lead to loss of homeostasis and neuronal dysfunction.
I also validated our findings in ALS patient tissue and explored disease relevant stress exposures in cellular models with altered STMN2 levels. Overall, this work identifies several overlapping mechanisms involved in STMN2 regulation in the cellular stress response. Dysregulation of one or more of these mechanisms may contribute to ALS development. Finally, I have made the first step to developing a screening assay for STMN2 by designing and testing a STMN2 splicing reporter.