Many neuronopathic diseases affecting the ageing population such as Alzheimer’s, Parkinson’s, Huntington’s, ALS with Frontotemporal dementia and Lewy body dementia all result from the aberrant accumulation of substrate in intracellular vesicles within cortical neurons. The result in neuronal cell death and wider neurinflammatory exacerbation in all cases. This diverse range of dementia-related diseases all result in similar neuropathology but the underlying molecular biology is poorly understood. It is recognised in all diseases, the process of intracellular recycling known as autophagy becomes chronically deregulated in affected neurons. This has many negative consequences on a cellular level although none have been definitively shown to directly result in disease. Most recently, a link between deregulated autophagy and DNA damage has been discovered (Wang et al. Mol Cell, 2016) and further, associated with neural degeneration (Walker et al. Nat Neurosci, 2018).
We propose a new hypothesis, based on the accumulation of DNA damage being the central cause of neural cell death in these dementia causing diseases, rather than the direct consequences of substrate accumulation.
Alzheimer’s disease neurons apoptose due to the accumulation of genomic mutations caused by aberrant autophagy, resulting in defective DNA repair mechanisms.
In this project we will apply state-of-the-art tools and technologies to investigate our hypothesis.
We have induced pluripotent stem cell (iPSC) lines derived from Alzheimer’s disease (AD) patients and age-matched control iPSC lines. These iPSC lines will be differentiated into structures called “brain organoids” and evaluated for the accumulation of genomic DNA double stranded breaks (DSB) under conditions that promote or block autophagy.
The AD and control iPSC lines will be genetically modified to either over-express or deplete the autophagic adaptor protein p62 in order to genetically modulate autophagy and assessed for the accumulation of DSB.
This will allow us to assess whether AD brain organoids accumulate DSB at a greater rate compared to controls and whether this is in a p62-dependent manner.
We will develop a series of small molecule inhibitors designed against the ubiquitination binding domain of p62 to functionally interrupt its nuclear inhibition of DSB repair mechanisms. These will be evaluated in vitro and, if successful, in vivo in established AD models at UCL.
This project will employ the latest enabling technologies to study AD in a human, disease-relevant model. If our hypothesis is proven, and we develop a small molecule to contextually disrupt p62 activity, this project could result in the development of a first line treatment for not only AD but potentially all age-related dementias.
Applicants must apply using the online form on the University Alliance website at https://unialliance.ac.uk/dta/cofund/how-to-apply-2/
. Full details of the programme, eligibility details and a list of available research projects can be seen at https://unialliance.ac.uk/dta/cofund/
The final deadline for application is 12 April 2019.