Novel Mutations in (TDP-43) in Patients with Familial Amyotrophic Lateral Sclerosis

English version České info

The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43–positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the ∼25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.

Vyšlo v časopise: Novel Mutations in (TDP-43) in Patients with Familial Amyotrophic Lateral Sclerosis. PLoS Genet 4(9): e32767. doi:10.1371/journal.pgen.1000193
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000193

Souhrn

Zdroje

1. AraiT

HasegawaM

AkiyamaH

IkedaK

NonakaT

2006 TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351 602 611

2. DavidsonY

KelleyT

MackenzieIR

Pickering-BrownS

Du PlessisD

2007 Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113 521 533

3. KwongLK

UryuK

TrojanowskiJQ

LeeVM

2008 TDP-43 proteinopathies: neurodegenerative protein misfolding diseases without amyloidosis. Neurosignals 16 41 51

4. NeumannM

SampathuDM

KwongLK

TruaxAC

MicsenyiMC

2006 Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314 130 133

5. WiderC

WszolekZK

2008 Etiology and pathophysiology of frontotemporal dementia, Parkinson disease and Alzheimer disease: lessons from genetic studies. Neurodegener Dis 5 122 125

6. WintonMJ

IgazLM

WongMM

KwongLK

TrojanowskiJQ

2008 Disturbance of nuclear and cytoplasmic Tar DNA binding protein (TDP-43) induces disease-like redistribution, sequestration and aggregate formation. J Biol Chem

7. ZhangYJ

XuYF

DickeyCA

BurattiE

BaralleF

2007 Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. J Neurosci 27 10530 10534

8. Amador-OrtizC

LinWL

AhmedZ

PersonettD

DaviesP

2007 TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann Neurol 61 435 445

9. FreemanSH

Spires-JonesT

HymanBT

GrowdonJH

FroschMP

2008 TAR-DNA binding protein 43 in Pick disease. J Neuropathol Exp Neurol 67 62 67

10. HigashiS

IsekiE

YamamotoR

MinegishiM

HinoH

2007 Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies. Brain Res 1184C 284 294

11. Nakashima-YasudaH

UryuK

RobinsonJ

XieSX

HurtigH

2007 Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol (Berl) 114 221 229

12. ProbstA

TaylorKI

TolnayM

2007 Hippocampal sclerosis dementia: a reappraisal. Acta Neuropathol 114 335 345

13. BurattiE

BaralleFE

2008 Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci 13 867 878

14. BurattiE

DorkT

ZuccatoE

PaganiF

RomanoM

2001 Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. Embo J 20 1774 1784

15. MercadoPA

AyalaYM

RomanoM

BurattiE

BaralleFE

2005 Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene. Nucleic Acids Res 33 6000 6010

16. GregoryRI

YanKP

AmuthanG

ChendrimadaT

DoratotajB

2004 The Microprocessor complex mediates the genesis of microRNAs. Nature 432 235 240

17. Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis (PARALS) 2001 Incidence of ALS in Italy: evidence for a uniform frequency in Western countries. Neurology 56 239 244

18. KunstCB

2004 Complex genetics of amyotrophic lateral sclerosis. Am J Hum Genet 75 933 947

19. RademakersR

HuttonM

2007 The genetics of frontotemporal lobar degeneration. Curr Neurol Neurosci Rep 7 434 442

20. RosenDR

SiddiqueT

PattersonD

FiglewiczDA

SappP

1993 Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362 59 62

21. MackenzieIR

BigioEH

IncePG

GeserF

NeumannM

2007 Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61 427 434

22. BakerM

MackenzieIR

Pickering-BrownSM

GassJ

RademakersR

2006 Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442 916 919

23. CrutsM

GijselinckI

van der ZeeJ

EngelborghsS

WilsH

2006 Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442 920 924

24. GassJ

CannonA

MackenzieIR

BoeveB

BakerM

2006 Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet 15 2988 3001

25. MoritaM

Al-ChalabiA

AndersenPM

HoslerB

SappP

2006 A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66 839 844

26. SkibinskiG

ParkinsonNJ

BrownJM

ChakrabartiL

LloydSL

2005 Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet 37 806 808

27. ValdmanisPN

DupreN

BouchardJP

CamuW

MeiningerV

2007 Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. Arch Neurol 64 240 245

28. VanceC

Al-ChalabiA

RuddyD

SmithBN

HuX

2006 Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2–21.3. Brain 129 868 876

29. WattsGD

WymerJ

KovachMJ

MehtaSG

MummS

2004 Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36 377 381

30. GitchoMA

BalohRH

ChakravertyS

MayoK

NortonJB

2008 TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol

31. SreedharanJ

BlairIP

TripathiVB

HuX

VanceC

2008 TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319 1668 1672

32. KabashiE

ValdmanisPN

DionP

SpiegelmanD

McConkeyBJ

2008 TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet

33. GoateA

Chartier-HarlinMC

MullanM

BrownJ

CrawfordF

1991 Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349 704 706

34. HuttonM

2001 Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms. Neurology 56 S21 25

35. Van DeerlinVM

LeverenzJB

BekrisLM

BirdTD

YuanW

2008 TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol

36. GijselinckI

SleegersK

EngelborghsS

RobberechtW

MartinJJ

2007 Neuronal inclusion protein TDP-43 has no primary genetic role in FTD and ALS. Neurobiol Aging

37. RollinsonS

SnowdenJS

NearyD

MorrisonKE

MannDM

2007 TDP-43 gene analysis in frontotemporal lobar degeneration. Neurosci Lett

38. SchumacherA

FriedrichP

Diehl-SchmidJ

IbachB

PerneczkyR

2007 No association of TDP-43 with sporadic frontotemporal dementia. Neurobiol Aging

39. Al-ChalabiA

AndersenPM

ChiozaB

ShawC

ShamPC

1998 Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor. Hum Mol Genet 7 2045 2050

40. PartonMJ

BroomW

AndersenPM

Al-ChalabiA

Nigel LeighP

2002 D90A-SOD1 mediated amyotrophic lateral sclerosis: a single founder for all cases with evidence for a Cis-acting disease modifier in the recessive haplotype. Hum Mutat 20 473