Understanding the Role of TDP-43 and FUS/TLS in ALS and Beyond

Overview

Journal Curr Opin Neurobiol

Specialties Biology
Neurology

Date 2011 Aug 5

PMID 21813273

Citations 205

Authors

Sandrine Da Cruz

Don W Cleveland

Affiliations

Soon will be listed here.

Abstract

Dominant mutations in two DNA/RNA binding proteins, TDP-43 and FUS/TLS, are causes of inherited Amyotrophic Lateral Sclerosis (ALS). TDP-43 and FUS/TLS have striking structural and functional similarities, implicating alterations in RNA processing as central in ALS. TDP-43 has binding sites within a third of all mouse and human mRNAs in brain and this binding influences the levels and splicing patterns of at least 20% of those mRNAs. Disease modeling in rodents of the first known cause of inherited ALS-mutation in the ubiquitously expressed superoxide dismutase (SOD1)-has yielded non-cell autonomous fatal motor neuron disease caused by one or more toxic properties acquired by the mutant proteins. In contrast, initial disease modeling for TDP-43 and FUS/TLS has produced highly varied phenotypes. It remains unsettled whether TDP-43 and FUS/TLS mutants provoke disease from a loss of function or gain of toxicity or both. TDP-43 or FUS/TLS misaccumulation seems central not just to ALS (where it is found in almost all instances of disease), but more broadly in neurodegenerative disease, including frontal temporal lobular dementia (FTLD-U) and many examples of Alzheimer's or Huntington's disease.

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References

Livet J, Weissman T, Kang H, Draft R, Lu J, Bennis R . Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature. 2007; 450(7166):56-62. DOI: 10.1038/nature06293. View

Huang C, Zhou H, Tong J, Chen H, Liu Y, Wang D . FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet. 2011; 7(3):e1002011. PMC: 3048370. DOI: 10.1371/journal.pgen.1002011. View

Sreedharan J, Blair I, Tripathi V, Hu X, Vance C, Rogelj B . TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008; 319(5870):1668-72. PMC: 7116650. DOI: 10.1126/science.1154584. View

Mackenzie I, Rademakers R, Neumann M . TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 2010; 9(10):995-1007. DOI: 10.1016/S1474-4422(10)70195-2. View

Buratti E, Brindisi A, Pagani F, Baralle F . Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance. Am J Hum Genet. 2004; 74(6):1322-5. PMC: 1182100. DOI: 10.1086/420978. View

Ling S, Albuquerque C, Han J, Lagier-Tourenne C, Tokunaga S, Zhou H . ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc Natl Acad Sci U S A. 2010; 107(30):13318-23. PMC: 2922163. DOI: 10.1073/pnas.1008227107. View

Xiao S, Sanelli T, Dib S, Sheps D, Findlater J, Bilbao J . RNA targets of TDP-43 identified by UV-CLIP are deregulated in ALS. Mol Cell Neurosci. 2011; 47(3):167-80. DOI: 10.1016/j.mcn.2011.02.013. View

Sephton C, Good S, Atkin S, Dewey C, Mayer 3rd P, Herz J . TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem. 2009; 285(9):6826-34. PMC: 2825476. DOI: 10.1074/jbc.M109.061846. View

Greenway M, Andersen P, Russ C, Ennis S, Cashman S, Donaghy C . ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet. 2006; 38(4):411-3. DOI: 10.1038/ng1742. View

10.

Ritson G, Custer S, Freibaum B, Guinto J, Geffel D, Moore J . TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97. J Neurosci. 2010; 30(22):7729-39. PMC: 2890254. DOI: 10.1523/JNEUROSCI.5894-09.2010. View

11.

Wegorzewska I, Bell S, Cairns N, Miller T, Baloh R . TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2009; 106(44):18809-14. PMC: 2762420. DOI: 10.1073/pnas.0908767106. View

12.

Stallings N, Puttaparthi K, Luther C, Burns D, Elliott J . Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol Dis. 2010; 40(2):404-14. DOI: 10.1016/j.nbd.2010.06.017. View

13.

Chiang P, Ling J, Jeong Y, Price D, Aja S, Wong P . Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc Natl Acad Sci U S A. 2010; 107(37):16320-4. PMC: 2941284. DOI: 10.1073/pnas.1002176107. View

14.

Fiesel F, Voigt A, Weber S, Van den Haute C, Waldenmaier A, Gorner K . Knockdown of transactive response DNA-binding protein (TDP-43) downregulates histone deacetylase 6. EMBO J. 2009; 29(1):209-21. PMC: 2808372. DOI: 10.1038/emboj.2009.324. View

15.

Strong M, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C . TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci. 2007; 35(2):320-7. DOI: 10.1016/j.mcn.2007.03.007. View

16.

Vance C, Rogelj B, Hortobagyi T, De Vos K, Nishimura A, Sreedharan J . Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009; 323(5918):1208-1211. PMC: 4516382. DOI: 10.1126/science.1165942. View

17.

Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H . TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006; 351(3):602-11. DOI: 10.1016/j.bbrc.2006.10.093. View

18.

Lu Y, Ferris J, Gao F . Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching. Mol Brain. 2009; 2:30. PMC: 2762964. DOI: 10.1186/1756-6606-2-30. View

19.

Momeni P, Schymick J, Jain S, Cookson M, Cairns N, Greggio E . Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD. BMC Neurol. 2006; 6:44. PMC: 1764752. DOI: 10.1186/1471-2377-6-44. View

20.

Feiguin F, Godena V, Romano G, DAmbrogio A, Klima R, Baralle F . Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Lett. 2009; 583(10):1586-92. DOI: 10.1016/j.febslet.2009.04.019. View