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

Sara Rollinson, Patrizia Rizzu, Stephen Sikkink, Matthew Baker, Nicola Halliwell, Julie Snowden, Bryan J. Traynor, Dina Ruano, Nigel Cairns, Jonathan D. Rohrer, Simon Mead, John Collinge, Martin Rossor, Ela Akay, Rita Guerreiro, Rosa Rademakers, Karen E. Morrison, Pau Pastor, Elena Alonso, Pablo Martinez-LageNeil Graff-Radford, David Neary, Peter Heutink, David M.A. Mann, John Van Swieten, Stuart M. Pickering-Brown

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)656-665
Number of pages10
JournalNeurobiology of aging
Volume30
Issue number4
DOIs
StatePublished - Apr 1 2009

Keywords

  • Frontotemporal lobar degeneration
  • Risk factor
  • TDP-43
  • UBAP1
  • Ubiquitin associated protein 1

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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    Rollinson, S., Rizzu, P., Sikkink, S., Baker, M., Halliwell, N., Snowden, J., Traynor, B. J., Ruano, D., Cairns, N., Rohrer, J. D., Mead, S., Collinge, J., Rossor, M., Akay, E., Guerreiro, R., Rademakers, R., Morrison, K. E., Pastor, P., Alonso, E., ... Pickering-Brown, S. M. (2009). Ubiquitin associated protein 1 is a risk factor for frontotemporal lobar degeneration. Neurobiology of aging, 30(4), 656-665. https://doi.org/10.1016/j.neurobiolaging.2009.01.009