Journal
NEUROBIOLOGY OF AGING
Volume 30, Issue 4, Pages 656-665Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2009.01.009
Keywords
Frontotemporal lobar degeneration; UBAP1; Ubiquitin associated protein 1; TDP-43; Risk factor
Categories
Funding
- Medical Research Council
- Alzheimers Research Trust
- NIH, National Institute on Aging [Z01-AG000949-02]
- National Institute of Neurological Disorders and Stroke
- Fundacao para a Ciencia e Tecnologia, Portugal [SFRH/BD/27442/2006]
- NIH [P50 AG16574]
- Pacific Alzheimer's Disease Research Foundation [C06-01]
- Government of Navarra
- MRC [MC_U123160651, MC_U123192748, G0400356, G0701441] Funding Source: UKRI
- Alzheimers Research UK [ART-EG2008A-2] Funding Source: researchfish
- Medical Research Council [MC_U123160651, G0701441, MC_U123192748, G0400356] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [SFRH/BD/27442/2006] Funding Source: FCT
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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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