Unlocking Disease-Modifying Treatments for TDP-43-Mediated Neurodegeneration

Abstract

Neurons degenerate in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causing progressive and inevitably fatal neurological decline. The best therapeutic strategies target underlying disease mediators, but after decades of intensive research, the causes of these neurodegenerative diseases remain elusive. Recently, coordinated activities of large consortia, increasing open access to large datasets, new methods such as cryo-transmission electron microscopy, and advancements in high-resolution omics technologies have offered new insights into the biology of disease that bring us closer to understanding mechanisms of neurodegeneration. In particular, improved understanding of the roles of the key pathological protein TAR DNA binding protein 43 (TDP-43) in disease has revealed intriguing new opportunities that provide hope for better diagnostic tools and effective treatments for ALS and FTD.

Keywords: TARDBP; chaperones; frontotemporal dementia; motor neuron disease; neurodegenerative disease; proteogenomics.

FIGURE 1

Early mechanisms of TDP‐43 neurodegeneration are the key to unlocking novel precision medicine and biomarkers for ALS and FTD. Loss of TDP‐43 from the nucleus results in a global change to RNA metabolism in the brain resulting in, at least in part, changes to alternative splicing and subsequent protein isoform usage, de novo protein synthesis, and protein loss, via nonsense‐mediated decay. This occurs concomitantly with an accumulation of cytoplasmic TDP‐43, which is prone to misfolding via aggregation pathways into diverse filaments and amorphous aggregates that are strongly associated with neurotoxicity. Existing foundational and future research investigating these early mechanisms of TDP‐43 dysfunction in ALS and FTD has been and will be instrumental in the discovery of strategies for precision medicine and diagnostic and prognostic biomarkers for these devastating disorders.