title: 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.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square House, London, UK.
authors.forename: Phillip
authors.initials: P
authors.lastname: Smethurst
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square House, London, UK.
authors.forename: Katie Claire Louise
authors.initials: KC
authors.lastname: Sidle
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square House, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D017096:Prion Diseases / Q000378:metabolism* / Q000473:pathology; D011328:Prions / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; D011328:Prions; C000598624:TARDBP protein, human
keywords: ALS; TDP-43; prion-like; propagation; seeding; strains