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TAR DNA-binding protein 43 in neurodegenerative disease

Abstract

In 2006, TAR DNA-binding protein 43 (TDP-43), a highly conserved nuclear protein, was identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and in the most common variant of frontotemporal lobar degeneration (FTLD), FTLD-U, which is characterized by cytoplasmic inclusions that stain positive for ubiquitin but negative for tau and α-synuclein. Since then, rapid advances have been made in our understanding of the physiological function of TDP-43 and the role of this protein in neurodegeneration. These advances link ALS and FTLD-U (now designated FTLD-TDP) to a shared mechanism of disease. In this Review, we summarize the current evidence regarding the normal function of TDP-43 and the TDP-43 pathology observed in FTLD-TDP, ALS, and other neurodegenerative diseases wherein TDP-43 pathology co-occurs with other disease-specific lesions (for example, with amyloid plaques and neurofibrillary tangles in Alzheimer disease). Moreover, we discuss the accumulating data that support our view that FTLD-TDP and ALS represent two ends of a spectrum of primary TDP-43 proteinopathies. Finally, we comment on the importance of recent advances in TDP-43-related research to neurological practice, including the new opportunities to develop better diagnostics and disease-modifying therapies for ALS, FTLD-TDP, and related disorders exhibiting TDP-43 pathology.

Key Points

  • Genetic and neuropathological evidence indicate that TAR DNA-binding protein 43 (TDP-43) is the main disease-associated protein in amyotrophic lateral sclerosis (ALS) and in many cases of frontotemporal lobar degeneration (FTLD)

  • FTLD with TDP-43 positive inclusions (FTLD-TDP) and ALS might represent two ends of a disease spectrum of primary TDP-43 proteinopathies

  • TDP-43 pathology seems to be a secondary feature of several neurodegenerative diseases, including Alzheimer disease, Parkinson disease and Huntington disease

  • Under physiological conditions, TDP-43 resides in the nuclear compartment and is involved in the regulation of gene expression

  • In neurodegenerative diseases, TDP-43 is primarily found in cytoplasmic inclusions, where the protein is poorly soluble, hyperphosphorylated, ubiquitinated, and cleaved into small fragments

  • Progress in TDP-43-related research has been rapid, with TDP-43 biomarkers and transgenic mouse models emerging within 3 years of the initial reports linking this protein to FTLD-TDP and ALS

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Figure 1: Physiological and pathophysiological TDP-43.
Figure 2: Domain structure and disease-associated mutations of TDP-43.
Figure 3: TDP-43 histopathology.
Figure 4: TDP-43 in FTLD and ALS.

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Chen-Plotkin, A., Lee, VY. & Trojanowski, J. TAR DNA-binding protein 43 in neurodegenerative disease. Nat Rev Neurol 6, 211–220 (2010). https://doi.org/10.1038/nrneurol.2010.18

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