Transactive response DNA-binding protein 43 (TDP-43) is a critical nuclear protein involved in the processing over 1,500 RNAs (the part of the genetic code that is translated into proteins) in neurons. Since the discovery that TDP-43 mis-located in 98% of people with ALS and half of those with frontotemporal dementia (FTD), TDP-43 has drawn interest as a key factor in the cause of these disorders.

In back-to-back papers published in Nature NeuroscienceHealey Center for ALS faculty member Clotilde Lagier-Tourenne, MD, PhD, and Healey Center Scientific Advisory Council (SAC) member Kevin Eggan, PhD, reported a major discovery on how TDP-43 causes motor neuron dysfunction. These studies support the development of novel therapeutic strategies for ALS and other neurodegenerative diseases affected by TDP-43 proteinopathy. The Healey Center SAC decided at the February 2019 meeting to accelerate this research by supporting the first two Healey Center scholars in the laboratories of Dr. Eggan and Dr. Lagier-Tourenne.

The research teams wanted to determine how TDP-43 reduction or dysfunction affects the expression of its RNA targets. Using two approaches to disrupt TDP-43 function in a human neuronal cell line, the researchers demonstrated that a reduction of TDP-43 strongly affects STMN2, which encodes stathmin-2, the protein most involved in nerve axon maintenance and regeneration after injury. Most importantly, the study showed that reduced stathmin-2 levels were identified in motor neurons from 13 out of 13 sporadic ALS patients and from four out of four patients with an expansion in the C9ORF72 gene, which is the most frequent genetic cause of ALS and frontotemporal dementia (FTD).

Given the role of stathmin-2 in neuronal maintenance and repair, the relationship between TDP-43 and stathmin-2 may represent a key mechanism driving ALS and FTD pathogenesis. The Healey Center research teams are working to develop approaches to restore stathmin-2 level as a therapeutic for ALS.

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