TDP-43 pathology: From noxious assembly to therapeutic removal

Our understanding of amyotrophic lateral sclerosis and frontotemporal dementia has advanced dramatically since the discovery of cytoplasmic TAR DNA-binding protein 43 (TDP-43) inclusions as the hallmark pathology of these neurodegenerative diseases. Recent studies have provided insights into the physiological function of TDP43 as an essential DNA-/RNA-modulating protein, and the triggers and consequences of TDP-43 dysfunction and aggregation. The formation of TDP-43 pathology is a progressive process, involving the generation of multiple distinct protein species, each with varying biophysical properties and roles in neurodegeneration. Here, we explore how the pathogenic changes to TDP-43, including mislocalisation, misfolding, aberrant liquid-liquid phase separation, stress granule assembly, oligomerisation, and post-translational modification, drive disease-associated aggregation in TDP-43 proteinopathies. We highlight how pathological TDP-43 species are formed and contribute to cellular dysfunction and toxicity, via both loss-of-function and gain-of-function mechanisms. We also review the role of protein homeostasis mechanisms, namely the ubiquitin proteasome system, autophagylysosome pathway, heat-shock response, and chaperone-mediated autophagy, in combating TDP-43 aggregation and discuss how their dysfunction likely promotes disease pathogenesis and progression. Finally, we evaluate preclinical studies aimed at enhancing TDP-43 protein clearance via these mechanisms and provide insight on promising strategies for future therapeutic advances. Harnessing the mechanisms that protect against or ameliorate TDP-43 pathology presents promising opportunities for developing disease-modifying treatments for these neurodegenerative diseases.