Is histone ubiquitination altered in Alzheimer's disease?

Project Details

Description

Alzheimer’s disease (AD) is the most common cause of neurodegeneration and there is currently no cure. The development of novel drugs to treat AD would benefit from a greater understanding of the novel molecular mechanisms underlying this disease.

We have strong evidence to suggest that the ubiquitination pathway is affected in a number of neurodegenerative disorders. Specifically, in collaboration with colleagues at the University of Edinburgh (Professor Tom Gillingwater and team), we have demonstrated that one component of this pathway, the Uba1 gene, is down regulated in spinal muscular atrophy (SMA), an incurable childhood muscular dystrophy (Wishart et al., 2014). Uba1 is one of two E1 ubiquitin ligases expressed in mammalian cells and by targeting this gene, we have successfully improved symptoms of SMA, with no detrimental effects (Powis et al., 2016).

Downregulation of Uba1 protein levels, and ubiquitin itself, are observations common to other neurodegenerative diseases (Groen and Gillingwater, 2015). Uba1 has been identified as a modifier of mutant huntingtin aggregation (Teuling et al., 2011)., while recently a link has been established between nuclear ubiquitin depletion, histone deubiquitination, an impaired DNA damage response (DDR) and disease associated protein aggregates (Ben et al., 2017).

Previous studies have indicated that there is a failure of the ubiquitin system in Alzheimer’s disease (AD), specifically reduced levels of cytoplasmic Uba1 were reported in AD brains (Lopez Salon et al., 2000).

Recently, expression of the BMI1 gene was reported to be reduced in AD brains leading to activation of GSK-3β (Flamier et al., 2018). BMI1 is known to promote ubiquitination of histone H2A (Li et al., 2005) and we have previously reported a link between expression of β-catenin (a target of GSK-3β) and ubiquitination in SMA (Wishart et al., 2014). This provides further support of a potential connection between ubiquitination and neurodegenerative disease.

It is now critical to establish the role of Uba1 and histone ubiquitination in AD and to determine the translational potential of ubiquitin targeting therapies in AD. Improving an impaired DDR (due to defects in ubiquitin homeostasis) may help to protect neurons in AD and also in other types of neurodegenerative disease.

To demonstrate this, in this study we propose to evaluate levels of Uba1 protein and ubiquitinated histones in AD using (clinically relevant) tissue from patients and a pre-clinical mouse model of AD (APP/PS1) (Radde et al., 2006).
StatusFinished
Effective start/end date1/06/1913/05/22

Funding

  • Alzheimer's Research UK: £5,000.00

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