Review: Prion-like mechanisms of transactive response DNA binding protein of 43 kDa (TDP-43) in amyotrophic lateral sclerosis (ALS)
- PMID: 25487060
- DOI: 10.1111/nan.12206
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.
Keywords: ALS; TDP-43; prion-like; propagation; seeding; strains.
© 2014 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
Similar articles
-
TDP-43 is consistently co-localized with ubiquitinated inclusions in sporadic and Guam amyotrophic lateral sclerosis but not in familial amyotrophic lateral sclerosis with and without SOD1 mutations.Neuropathology. 2009 Dec;29(6):672-83. doi: 10.1111/j.1440-1789.2009.01029.x. Epub 2009 Jun 3. Neuropathology. 2009. PMID: 19496940
-
In vitro prion-like behaviour of TDP-43 in ALS.Neurobiol Dis. 2016 Dec;96:236-247. doi: 10.1016/j.nbd.2016.08.007. Epub 2016 Aug 30. Neurobiol Dis. 2016. PMID: 27590623 Free PMC article.
-
Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam.Acta Neuropathol. 2008 Jan;115(1):133-45. doi: 10.1007/s00401-007-0257-y. Epub 2007 Aug 23. Acta Neuropathol. 2008. PMID: 17713769
-
The prion-like nature of amyotrophic lateral sclerosis.Prog Mol Biol Transl Sci. 2020;175:261-296. doi: 10.1016/bs.pmbts.2020.07.002. Epub 2020 Sep 1. Prog Mol Biol Transl Sci. 2020. PMID: 32958236 Review.
-
From molecule to molecule and cell to cell: prion-like mechanisms in amyotrophic lateral sclerosis.Neurobiol Dis. 2015 May;77:257-65. doi: 10.1016/j.nbd.2015.02.009. Epub 2015 Feb 17. Neurobiol Dis. 2015. PMID: 25701498 Review.
Cited by
-
Dynamic characterization and interpretation for protein-RNA interactions across diverse cellular conditions using HDRNet.Nat Commun. 2023 Oct 26;14(1):6824. doi: 10.1038/s41467-023-42547-1. Nat Commun. 2023. PMID: 37884495 Free PMC article.
-
TDP-43 and tau concurrence in the entorhinal subfields in primary age-related tauopathy and preclinical Alzheimer's disease.Brain Pathol. 2023 Jul;33(4):e13159. doi: 10.1111/bpa.13159. Epub 2023 Apr 10. Brain Pathol. 2023. PMID: 37037195 Free PMC article.
-
Evolution of sequence traits of prion-like proteins linked to amyotrophic lateral sclerosis (ALS).PeerJ. 2022 Nov 17;10:e14417. doi: 10.7717/peerj.14417. eCollection 2022. PeerJ. 2022. PMID: 36415860 Free PMC article.
-
Expanding the TDP-43 Proteinopathy Pathway From Neurons to Muscle: Physiological and Pathophysiological Functions.Front Neurosci. 2022 Feb 3;16:815765. doi: 10.3389/fnins.2022.815765. eCollection 2022. Front Neurosci. 2022. PMID: 35185458 Free PMC article. Review.
-
Dysfunction of RNA/RNA-Binding Proteins in ALS Astrocytes and Microglia.Cells. 2021 Nov 3;10(11):3005. doi: 10.3390/cells10113005. Cells. 2021. PMID: 34831228 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Miscellaneous