Molecular, functional, and pathological aspects of TDP-43 fragmentation

Deepak Chhangani; Alfonso Martín-Peña; Diego E Rincon-Limas

doi:10.1016/j.isci.2021.102459

Molecular, functional, and pathological aspects of TDP-43 fragmentation

iScience. 2021 Apr 21;24(5):102459. doi: 10.1016/j.isci.2021.102459. eCollection 2021 May 21.

Authors

Deepak Chhangani¹, Alfonso Martín-Peña¹, Diego E Rincon-Limas^{1

2

3}

Affiliations

¹ Department of Neurology, McKnight Brain Institute, and Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL 32611, USA.
² Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32611, USA.
³ Genetics Institute, University of Florida, Gainesville, FL 32611, USA.

Abstract

Transactive response DNA binding protein 43 (TDP-43) is a DNA/RNA binding protein involved in transcriptional regulation and RNA processing. It is linked to sporadic and familial amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 is predominantly nuclear, but it translocates to the cytoplasm under pathological conditions. Cytoplasmic accumulation, phosphorylation, ubiquitination and truncation of TDP-43 are the main hallmarks of TDP-43 proteinopathies. Among these processes, the pathways leading to TDP-43 fragmentation remain poorly understood. We review here the molecular and biochemical properties of several TDP-43 fragments, the mechanisms and factors mediating their production, and their potential role in disease progression. We also address the presence of TDP-43 C-terminal fragments in several neurological disorders, including Alzheimer's disease, and highlight their respective implications. Finally, we discuss features of animal models expressing TDP-43 fragments as well as recent therapeutic strategies to approach TDP-43 truncation.

Keywords: Biological sciences; Molecular biology; Molecular interaction; Molecular physiology.

Publication types

Review

Grants and funding

R01 AG059871/AG/NIA NIH HHS/United States