TDP-43 and the neurodegenerative diseases puzzle
DOI:
https://doi.org/10.22201/ceide.16076079e.2026.27.3.4Keywords:
TDP43, neurodegeneration, amyotrophic lateral sclerosis, frontotemporal dementia, mixed proteinopathyAbstract
TDP-43 is an essential protein for neuronal function. Under normal conditions, it is located in the cell nucleus, where it helps regulate gene expression and maintain RNA homeostasis. In several neurodegenerative diseases, however, it can relocate to the cytoplasm, accumulate abnormally, and undergo chemical modifications that alter its structure and function, ultimately contributing to cellular dysfunction and death. The abnormal accumulation of tdp-43 is a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia, but it is also found in disorders such as Alzheimer’s and Parkinson’s diseases. In these conditions, it often coexists with other misfolded proteins, including tau, β-amyloid, and α-synuclein, giving rise to what are known as mixed proteinopathies. This article proposes an integrative perspective that positions tdp-43 as a central player in multiple neurodegenerative processes. A better understanding of its cellular dynamics and the mechanisms that promote its aggregation may contribute to the development of new therapeutic strategies for these complex disorders.
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