TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

Overview

Journal Science

Specialty Science

Date 2008 Mar 1

PMID 18309045

Citations 1287

Authors

Jemeen Sreedharan

Ian P Blair

Vineeta B Tripathi

Xun Hu

Caroline Vance

Boris Rogelj

Steven Ackerley

Jennifer C Durnall

Kelly L Williams

Emanuele Buratti

Francisco Baralle

Jacqueline de Belleroche

J Douglas Mitchell

P Nigel Leigh

Ammar Al-Chalabi

Christopher C Miller

Garth Nicholson

Christopher E Shaw

Affiliations

Soon will be listed here.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

Citing Articles

Mechanisms underlining R-loop biology and implications for human disease.

Liu J, Li F, Cao Y, Lv Y, Lei K, Tu Z Front Cell Dev Biol. 2025; 13:1537731.

PMID: 40061014 PMC: 11885306. DOI: 10.3389/fcell.2025.1537731.

Structural and functional studies of the VAPB-PTPIP51 ER-mitochondria tethering proteins in neurodegenerative diseases.

Blair K, Martinez-Serra R, Gosset P, Martin-Guerrero S, Morotz G, Atherton J Acta Neuropathol Commun. 2025; 13(1):49.

PMID: 40045432 PMC: 11881430. DOI: 10.1186/s40478-025-01964-7.

Epigenetic regulation of TDP-43: potential implications for amyotrophic lateral sclerosis.

Mengistu D, Terribili M, Pellacani C, Ciapponi L, Marzullo M Front Mol Med. 2025; 5:1530719.

PMID: 40017539 PMC: 11865237. DOI: 10.3389/fmmed.2025.1530719.

TMEM106B deficiency leads to alterations in lipid metabolism and obesity in the TDP-43 knock-in mouse model.

Yang C, Lee G, Hao L, Hu F Commun Biol. 2025; 8(1):315.

PMID: 40011708 PMC: 11865606. DOI: 10.1038/s42003-025-07752-2.

Advancements in genetic research and RNA therapy strategies for amyotrophic lateral sclerosis (ALS): current progress and future prospects.

Ruffo P, Traynor B, Conforti F J Neurol. 2025; 272(3):233.

PMID: 40009238 PMC: 11865122. DOI: 10.1007/s00415-025-12975-8.

References

Mishra M, Paunesku T, Woloschak G, Siddique T, Zhu L, Lin S . Gene expression analysis of frontotemporal lobar degeneration of the motor neuron disease type with ubiquitinated inclusions. Acta Neuropathol. 2007; 114(1):81-94. DOI: 10.1007/s00401-007-0240-7. View

Rollinson S, Snowden J, Neary D, Morrison K, Mann D, Pickering-Brown S . TDP-43 gene analysis in frontotemporal lobar degeneration. Neurosci Lett. 2007; 419(1):1-4. DOI: 10.1016/j.neulet.2007.03.044. View

Brooks B, Miller R, Swash M, Munsat T . El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2001; 1(5):293-9. DOI: 10.1080/146608200300079536. View

Buratti E, Baralle F . Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci. 2007; 13:867-78. DOI: 10.2741/2727. View

Schumacher A, Friedrich P, Diehl-Schmid J, Ibach B, Eisele T, Laws S . No association of chromatin-modifying protein 2B with sporadic frontotemporal dementia. Neurobiol Aging. 2006; 28(11):1789-90. DOI: 10.1016/j.neurobiolaging.2006.07.016. View

Rothstein J . TDP-43 in amyotrophic lateral sclerosis: pathophysiology or patho-babel?. Ann Neurol. 2007; 61(5):382-4. DOI: 10.1002/ana.21155. View

Nakashima-Yasuda H, Uryu K, Robinson J, Xie S, Hurtig H, Duda J . Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol. 2007; 114(3):221-9. DOI: 10.1007/s00401-007-0261-2. View

Sapp P, Hosler B, McKenna-Yasek D, Chin W, Gann A, Genise H . Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am J Hum Genet. 2003; 73(2):397-403. PMC: 1180377. DOI: 10.1086/377158. View

Neumann M, Sampathu D, Kwong L, Truax A, Micsenyi M, Chou T . Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006; 314(5796):130-3. DOI: 10.1126/science.1134108. View

10.

Freeman S, Spires-Jones T, Hyman B, Growdon J, Frosch M . TAR-DNA binding protein 43 in Pick disease. J Neuropathol Exp Neurol. 2007; 67(1):62-7. DOI: 10.1097/nen.0b013e3181609361. View

11.

Hasegawa M, Arai T, Akiyama H, Nonaka T, Mori H, Hashimoto T . TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. Brain. 2007; 130(Pt 5):1386-94. DOI: 10.1093/brain/awm065. View

12.

Shaw C, Enayat Z, Powell J, Anderson V, Radunovic A, Al-Sarraj S . Familial amyotrophic lateral sclerosis. Molecular pathology of a patient with a SOD1 mutation. Neurology. 1997; 49(6):1612-6. DOI: 10.1212/wnl.49.6.1612. View

13.

Buratti E, Brindisi A, Giombi M, Tisminetzky S, Ayala Y, Baralle F . TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing. J Biol Chem. 2005; 280(45):37572-84. DOI: 10.1074/jbc.M505557200. View

14.

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

15.

Lipton A, White 3rd C, Bigio E . Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration. Acta Neuropathol. 2004; 108(5):379-85. DOI: 10.1007/s00401-004-0900-9. View

16.

Gurney M, Pu H, Chiu A, Dal Canto M, Polchow C, Alexander D . Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science. 1994; 264(5166):1772-5. DOI: 10.1126/science.8209258. View

17.

Morita M, Al-Chalabi A, Andersen P, Hosler B, Sapp P, Englund E . A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology. 2006; 66(6):839-44. DOI: 10.1212/01.wnl.0000200048.53766.b4. View

18.

Rosen D, Siddique T, Patterson D, Figlewicz D, Sapp P, Hentati A . Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993; 362(6415):59-62. DOI: 10.1038/362059a0. View

19.

Ghadge G, Wang L, Sharma K, Monti A, Bindokas V, Stevens F . Truncated wild-type SOD1 and FALS-linked mutant SOD1 cause neural cell death in the chick embryo spinal cord. Neurobiol Dis. 2005; 21(1):194-205. DOI: 10.1016/j.nbd.2005.07.006. View

20.

Shaw C, Al-Chalabi A, Leigh N . Progress in the pathogenesis of amyotrophic lateral sclerosis. Curr Neurol Neurosci Rep. 2002; 1(1):69-76. DOI: 10.1007/s11910-001-0078-7. View