Imagine a conductor leading an orchestra, ensuring that every musician plays their part in harmony. The TAR DNA binding protein 43 kDa (TDP-43) plays a similar role in our cells, orchestrating essential functions. However, when TDP-43 goes awry, it can set off a chain reaction of dysfunction that may contribute to neurodegenerative diseases like ALS and FTLD. Recent research has explored the intricate mechanisms behind TDP-43 pathology and has revealed that dysregulation of this protein can trigger a cascade of events, impairing gene expression, mRNA stability, and the coordination of key cell pathways. Surprisingly, the notable features of TDP-43 pathology, such as abnormal protein accumulation, may actually be signs of an underlying disruption to TDP-43’s regular function. This mini-review highlights our current understanding of both normal and pathological aspects of TDP-43 and uncovers potential mechanisms driving its involvement in neurodegeneration. By delving into this fascinating research, we can shed light on the complexities of TDP-43 dysfunction and pave the way for new therapeutic strategies.

TAR DNA binding protein 43 kDa (TDP-43) plays an important role in several essential cell functions. However, TDP-43 dysfunction has been implicated in the development of various brain diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Recent investigations into the individual components of TDP-43 pathology show how broader TDP-43 dysfunction may precede these disease end states, and therefore could help to explain why TDP-43 dysfunction continues to be implicated in a rapidly expanding category of neurodegenerative diseases. The literature reviewed in this article suggests that dysregulation of TDP-43 initiated by some environmental and/or genetic insults can lead to a snowballing dysfunction across the cell, involving impaired gene expression, mRNA stability, as well as the function and coordination of those pathways directly regulated by TDP-43. Furthermore, the hallmarks of TDP-43 pathology, such as hyperphosphorylation and insoluble cytoplasmic accumulation of the protein may actually be artifacts of an upstream impairment in TDP-43’s normal function. Overall, the present article summarizes current knowledge regarding TDP-43’s normal and pathological cell functions and sheds light on possible mechanisms that underlie its causal role in neurodegeneration.

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