Structure, Function, Pathomechanisms and Targeting of TDP-43 in Neurodegeneration.

Brain research 2026

Zhang X, Zhang B, Shang Y, Zou L

Abstract

The TDP-43 protein has a significant relationship to the aetiology of neurodegenerative disorders. Based on its protein structure, protein modification and RNA function, this study analysed its various biological effects and the pathological effects of these biological effects in neurodegenerative diseases. It was found that TDP-43 protein undergoes conformational changes and functional alterations through protein phosphorylation, ubiquitination, SUMOylation, and acetylation, promoting its removal from the nucleus and transforming it from a normal, functional protein to an abnormally aggregated, pathological protein. It is involved in oxidative stress, inflammatory response, autophagy, angiogenesis and other biological effects. Furthermore, investigations have demonstrated that the TDP-43 protein is directly associated with neuronal growth, axon guidance, and synaptic activity, suggesting it may potentially play a significant role in the onset of degenerative neurological conditions. Based on this, the treatment strategy and future research direction are outlined to provide some insights into understanding the pathogenic mechanisms of neurodegenerative disorders and potential treatment approaches.

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