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. 2009 Apr;30(4):656-65.
doi: 10.1016/j.neurobiolaging.2009.01.009. Epub 2009 Feb 12.

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

Sara Rollinson  1 , 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-Lage, Neil Graff-Radford, David Neary, Peter Heutink, David M A Mann, John Van Swieten, Stuart M Pickering-Brown
Affiliations

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

Sara Rollinson et al. Neurobiol Aging. 2009 Apr.

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.

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Figures

Figure 1
Figure 1
Sliding window analysis (haplotype size N=2 to N-7) generated with Haplo.score of the SNPs compromising the genomic region containing UBAP1 in the Manchester FTLD cohort. Green line equivalent to P=0.05.
Figure 2
Figure 2
Immunohistological analysis of UBAP1 in a case of familial FTLD(Momeni et al., 2006). UBAP1 positive neuronal cytoplasmic inclusions (arrows) in (a) frontal cortex and (b) hippocampus. Confocal analysis of UBAP1 (c,g) and TDP-43 (d,h) with merged images (f,j) demonstrating co-localisation.
Figure 3
Figure 3
Relative expression of UBAP1 mRNA in Manchester FTLD brain tissue analysed by UBAP1 haplotype. N values indicate observations not individuals.
See this image and copyright information in PMC

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