Review: Prion-like mechanisms of transactive response DNA binding protein of 43 kDa (TDP-43) in amyotrophic lateral sclerosis (ALS).

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal devastating neurodegenerative disorder which predominantly affects the motor neurons in the brain and spinal cord. The death of the motor neurons in ALS causes subsequent muscle atrophy, paralysis and eventual death. Clinical and biological evidence now demonstrates that ALS has many similarities to prion disease in terms of disease onset, phenotype variability and progressive spread. The pathognomonic ubiquitinated inclusions deposited in the neurons and glial cells in brains and spinal cords of patients with ALS and fronto-temporal lobar degeneration with ubiquitinated inclusions contain aggregated transactive response DNA binding protein of 43 kDa (TDP-43), and evidence now suggests that TDP-43 has cellular prion-like properties. The cellular mechanisms of prion protein misfolding and aggregation are thought to be responsible for the characteristics of prion disease. Therefore, there is a strong mechanistic basis for a prion-like behaviour of the TDP-43 protein being responsible for some characteristics of ALS. In this review, we compare the prion-like mechanisms of TDP-43 to the clinical and biological nature of ALS in order to investigate how this protein could be responsible for some of the characteristic properties of the disease.

• Authors: Phillip Smethurst, Katie Claire Louise Sidle, John Hardy
• Journal: Neuropathology and applied neurobiology (Neuropathol Appl Neurobiol) Vol. 41 Issue 5 Pg. 578-97 (Aug 2015) ISSN: 1365-2990 [Electronic] England
• PMID: 25487060 (Publication Type: Journal Article, Review)
• Copyright: © 2014 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.

Chemical References

• DNA-Binding Proteins
• Prions
• TARDBP protein, human

Topics

• Amyotrophic Lateral Sclerosis (metabolism, pathology)
• Animals
• Brain (metabolism, pathology)
• DNA-Binding Proteins (metabolism)
• Humans
• Inclusion Bodies (metabolism, pathology)
• Motor Neurons (metabolism, pathology)
• Neuroglia (metabolism, pathology)
• Prion Diseases (metabolism, pathology)
• Prions (metabolism)
• Spinal Cord (metabolism, pathology)