Contribution of TARDBP to Alzheimer's Disease Genetic Etiology

被引:19
作者
Brouwers, Nathalie [1 ,2 ,3 ]
Bettens, Karolien [1 ,2 ,3 ]
Gijselinck, Ilse [1 ,2 ,3 ]
Engelborghs, Sebastiaan [3 ,4 ,5 ,6 ]
Pickut, Barbara A. [5 ,6 ]
Van Miegroet, Helen [1 ,2 ,3 ]
Montoya, Ana Gil [1 ,2 ,3 ]
Mattheijssens, Maria [1 ,2 ,3 ]
Peeters, Karin [1 ,2 ,3 ]
De Deyn, Peter P. [3 ,4 ,5 ,6 ]
Cruts, Marc [1 ,2 ,3 ]
Sleegers, Kristel [1 ,2 ,3 ]
Van Broeckhoven, Christine [1 ,2 ,3 ]
机构
[1] Univ Antwerp VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, B-2610 Antwerp, Belgium
[2] Inst Born Bunge, Neurogenet Lab, Antwerp, Belgium
[3] Univ Antwerp, B-2020 Antwerp, Belgium
[4] Inst Born Bunge, Lab Neurochem & Behav, Antwerp, Belgium
[5] ZNA Middelheim, Div Neurol, Antwerp, Belgium
[6] ZNA Middelheim, Memory Clin, Antwerp, Belgium
关键词
Alzheimer's disease; association analysis; genetics; mutation analysis; TARDBP; AMYOTROPHIC-LATERAL-SCLEROSIS; FRONTOTEMPORAL LOBAR DEGENERATION; DNA-BINDING; NO ASSOCIATION; LEWY BODIES; IN-VITRO; TDP-43; DEMENTIA; NUCLEAR; PATHOLOGY;
D O I
10.3233/JAD-2010-100198
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The nuclear transactive response (TAR) DNA binding protein-43, TDP-43, is a major constituent of the ubiquitinated neuronal inclusions in patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Missense mutations in TDP-43 have been associated with familial and sporadic ALS. Since TDP-43 immunoreactivity was also frequently observed in Alzheimer's disease (AD) brains and elevated TDP-43 plasma levels were detected in a subset of AD patients, we sequenced the TDP-43 gene, TARDBP, in a well-documented group of AD patients (n =485). We observed one mutation in exon 3 (c.269C>T) predicting a p.Ala90Val substitution in two patients. One extra p.Ala90Val carrier was observed by sequencing exon 3 of an additional set of 254 AD patients. The mutation was absent from 604 control individuals. Allele and haplotype analysis using microsatellite markers suggested that the three patients might share a common founder. However, co-segregation of p.Ala90Val with AD could not be realized leaving its pathogenic unclear at this moment. Also, sequencing in 190 additional AD patients of TARDBP exon 6 in which pathogenic mutations have been reported in FTLD and ALS was negative. Further, genetic association analyses using five single nucleotide polymorphisms did not detect significant differences between AD patients and control individuals. In conclusion, the genetic contribution of TARDBP to AD was restricted to the rare mutation p.Ala90Val (3/739, 0.4%) of unclear pathogenic nature that affects the nuclear localization signal in TDP-43.
引用
收藏
页码:423 / 430
页数:8
相关论文
共 32 条
[1]   TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease [J].
Amador-Ortiz, Catalina ;
Lin, Wen-Lang ;
Ahmed, Zeshan ;
Personett, David ;
Davies, Peter ;
Dara, Ranjan ;
Graff-Radford, Neill R. ;
Hutton, Michael L. ;
Dickson, Dennis W. .
ANNALS OF NEUROLOGY, 2007, 61 (05) :435-445
[2]   TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis [J].
Arai, Tetsuaki ;
Hasegawa, Masato ;
Akiyama, Haruhiko ;
Ikeda, Kenji ;
Nonaka, Takashi ;
Mori, Hiroshi ;
Mann, David ;
Tsuchiya, Kuniaki ;
Yoshida, Marl ;
Hashizume, Yoshio ;
Oda, Tatsuro .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2006, 351 (03) :602-611
[3]   Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies [J].
Arai, Tetsuaki ;
Mackenzie, Ian R. A. ;
Hasegawa, Masato ;
Nonoka, Takashi ;
Niizato, Kazhuhiro ;
Tsuchiya, Kuniaki ;
Iritani, Shuji ;
Onaya, Mitsumoto ;
Akiyama, Haruhiko .
ACTA NEUROPATHOLOGICA, 2009, 117 (02) :125-136
[4]   Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease [J].
Brouwers, Nathalie ;
Sleegers, Kristel ;
Engelborghs, Sebastiaan ;
Bogaerts, Veerle ;
Serneels, Sally ;
Kamali, Kenan ;
Corsmit, Ellen ;
De Leenheir, Evelyn ;
Martin, Jean-Jacques ;
De Deyn, Peter P. ;
Van Broeckhoven, Christine ;
Theuns, Jessie .
BRAIN, 2006, 129 :2984-2991
[5]   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].
Buratti, E ;
Brindisi, A ;
Giombi, M ;
Tisminetzky, S ;
Ayala, YM ;
Baralle, FE .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (45) :37572-37584
[6]   Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping [J].
Buratti, E ;
Dörk, T ;
Zuccato, E ;
Pagani, F ;
Romano, M ;
Baralle, FE .
EMBO JOURNAL, 2001, 20 (07) :1774-1784
[7]  
DE DEYN PP, 2005, INT J GERIATR PSYCH, V20, P70
[8]   Dose dependent effect of APOE ε4 on behavioral symptoms in frontal lobe dementia [J].
Engelborghs, S ;
Dermaut, B ;
Mariën, P ;
Symons, A ;
Vloeberghs, E ;
Maertens, K ;
Somers, N ;
Goeman, J ;
Rademakers, R ;
Van den Broeck, M ;
Pickut, B ;
Cruts, M ;
Van Broeckhoven, C ;
De Deyn, PP .
NEUROBIOLOGY OF AGING, 2006, 27 (02) :285-292
[9]   Prospective Belgian study of neurodegenerative and vascular dementia:: APOE genotype effects [J].
Engelborghs, S ;
Dermaut, B ;
Goeman, J ;
Saerens, J ;
Mariën, P ;
Pickut, BA ;
Van den Broeck, M ;
Serneels, S ;
Cruts, M ;
Van Broeckhoven, C ;
De Deyn, PP .
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 2003, 74 (08) :1148-1151
[10]   No association of CSF biomarkers with APOEε4, plaque and tangle burden in definite Alzheimer's disease [J].
Engelborghs, Sebastiaan ;
Sleegers, Kristel ;
Cras, Patrick ;
Brouwers, Nathalie ;
Serneels, Sally ;
De Leenheir, Evelyn ;
Martin, Jean-Jacques ;
Vanmechelen, Eugeen ;
Van Broeckhoven, Christine ;
De Deyn, Peter Paul .
BRAIN, 2007, 130 :2320-2326