TDP-43 Proteinopathy and Tauopathy: Do They Have Pathomechanistic Links?

Int J Mol Sci. 2022 Dec 12;23(24):15755. doi: 10.3390/ijms232415755.

Abstract

Transactivation response DNA binding protein 43 kDa (TDP-43) and tau are major pathological proteins of neurodegenerative disorders, of which neuronal and glial aggregates are pathological hallmarks. Interestingly, accumulating evidence from neuropathological studies has shown that comorbid TDP-43 pathology is observed in a subset of patients with tauopathies, and vice versa. The concomitant pathology often spreads in a disease-specific manner and has morphological characteristics in each primary disorder. The findings from translational studies have suggested that comorbid TDP-43 or tau pathology has clinical impacts and that the comorbid pathology is not a bystander, but a part of the disease process. Shared genetic risk factors or molecular abnormalities between TDP-43 proteinopathies and tauopathies, and direct interactions between TDP-43 and tau aggregates, have been reported. Further investigations to clarify the pathogenetic factors that are shared by a broad spectrum of neurodegenerative disorders will establish key therapeutic targets.

Keywords: AD; ALS; CBD; FTLD; LATE; PART; PSP; SFPQ; TDP-43; tau.

Publication types

  • Review

MeSH terms

  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Frontotemporal Lobar Degeneration* / metabolism
  • Humans
  • Neurodegenerative Diseases*
  • TDP-43 Proteinopathies* / metabolism
  • Tauopathies* / genetics
  • Tauopathies* / pathology
  • tau Proteins / genetics
  • tau Proteins / metabolism

Substances

  • tau Proteins
  • DNA-Binding Proteins