Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration

NEUROBIOLOGY OF AGING

卷:30

Article

Rollinson, Sara¹  Rizzu, Patrizia²  Sikkink, Stephen¹  Baker, Matthew³  Halliwell, Nicola¹  Snowden, Julie⁴  Traynor, Bryan J.⁵  Ruano, Dina²  Cairns, Nigel^6,7  Rohrer, Jonathan D.⁸  Mead, Simon⁹  Collinge, John⁹  Rossor, Martin⁸  Akay, Ela¹  Guerreiro, Rita^5,10  Rademakers, Rosa³  Morrison, Karen E.^11,12  Pastor, Pau^13,14  Alonso, Elena^13,14  Martinez-Lage, Pablo¹⁵  Graff-Radford, Neil³  Neary, David⁴  Heutink, Peter²  Mann, David M. A.⁴  Van Swieten, John¹⁶  Pickering-Brown, Stuart M.¹ 

[1] Univ Manchester, Fac Human & Med Sci, Manchester M13 9PT, Lancs, England

[2] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, Netherlands

[3] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[4] Univ Manchester, Ctr Clin Neurosci, Greater Manchester Neurosci Ctr, Hope Hosp, Salford M6 8HD, Lancs, England

[5] NIA, Neurogenet Lab, Neurogenet Branch, Natl Inst Neurol Disorders & Stroke,NIH, Bethesda, MD 20892 USA

[6] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA

[7] Washington Univ, Sch Med, Rush Alzheimers Dis Ctr, St Louis, MO USA

[8] Dementia Res Ctr, Inst Neurol, London WC1N 3BG, England

[9] UCL Inst Neurol, MRC Prion Unit, Dept Neurodegenerat Dis, London WC1N 3BG, England

[10] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal

[11] Univ Birmingham, Sch Med, Dept Clin Neurosci, Div Neurosci, Birmingham B15 2TT, W Midlands, England

[12] Univ Hosp Birmingham NHS Fdn Trust, Queen Elizabeth Hosp, Birmingham B15 2TH, W Midlands, England

[13] Ctr Appl Med Res CIMA, Neurogenet Lab, Div Neurosci, Pamplona, Spain

[14] Univ Navarra, Sch Med, Dept Neurol, E-31080 Pamplona, Spain

[15] ACE, Barcelona, Spain

[16] Erasmus MC, Rotterdam, Netherlands

关键词: Frontotemporal lobar degeneration;    UBAP1;    Ubiquitin associated protein 1;    TDP-43;    Risk factor;   

DOI  :  10.1016/j.neurobiolaging.2009.01.009

来源: Elsevier

【 摘 要 】

Frontotemporal lobar degeneration (FTLD) is now recognised as a common form of early onset dementia. Up to 40% of patients have a family history of disease demonstrating a large genetic component to its etiology. Linkage to chromosome 9p21 has recently been reported in families with this disorder. We undertook a large scale two-stage linkage disequilibrium mapping approach of this region in the Manchester FTLD cohort. We identified association of ubiquitin associated protein 1 (UBAP1; OR 1.42 95% CI 1.08-1.88, P = 0.013) with FTLD in this cohort and we replicated this finding in an additional two independent cohorts from the Netherlands (OR 1.33 95% CI 1.04-1.69, P = 0.022), the USA (OR 1.4 95% CI 1.02-1.92, P = 0.032) and a forth Spanish cohort approached significant association (OR 1.45 95% CI 0.97-2.17, P = 0.064). However, we failed to replicate in a fifth cohort from London (OR 0.99 95% CI 0.72-1.37, P = 0.989). Quantitative analysis of UBAP1 mRNA extracted from tissue from the Manchester cases demonstrated a significant reduction of expression from the disease-associated haplotype. In addition, we identified a case of familial FTLD that demonstrated colocalisation of UBAP1 and TDP-43 in the neuronal cytoplasmic inclusions in the brain of this individual. Our data for the first time identifies UBAP1 as a genetic risk factor for FTLD and suggests a mechanistic relationship between this protein and TDP-43. (C) 2009 Elsevier Inc. All rights reserved.

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