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Does reduction of wild-type huntingtin in the adult brain affect cognitive function?


   Cardiff School of Biosciences

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  Dr Mariah Lelos  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Huntington’s disease (HD) is a fatal, devastating neurological disorder characterised by complex motor, cognitive and neuropsychiatric symptoms. HD is caused by an autosomal dominant mutation in the HTT gene on chromosome 4. The mutant huntingtin (mHtt) protein confers a predominant toxic gain-of-function in HD, which is hypothesised to underlie the neuronal degeneration observed in HD patients. No disease-modifying treatments exist for HD, but genetic huntingtin-lowering strategies are being explored in preclinical and early Phase I/II clinical trials. Many of these strategies seek to lower the toxic mHtt, but many approaches non-specifically lower both wild-type and mHtt. Importantly, it has been speculated that any loss-of-function that occurs with reduction of wild-type Htt may also contribute to the disease progression and have a significant impact on the welfare of HD patients. Indeed, a recent Roche trial of Tominersen (an antisense oligonucleotide that aims to knockdown wild-type and mutant Htt) had to be halted due to safety concerns. This again raises the question as to whether loss of wild-type Htt in the adult brain may be detrimental to patients.

Despite the HTT gene being central to the development of HD, the normal function of HTT/Htt gene/protein is still not fully known. Htt has been suggested to be involved in several cellular processes, including neural development, with knockout of HTT proving to be embryonically lethal. Less is known about the role of Htt in the adult brain, although involvement of Htt in immune function and cell signalling have been proposed. 

Thus, a number of outstanding questions remain regarding the role of wild-type Htt in the adult brain and the functional impact of lowering wildtype Htt. The overall aim of this project is to determine whether lowering wild-type Htt has an impact of cognitive or neuropsychiatric function. Using a novel CAG-Cre TAM-inducible Htt knockdown mouse model, we will lower Htt in the adult mouse (>85% reduction in striatum and cortex, from 2 months of age). We will use a battery of sensitive cognitive assays to reveal the long-term effect on visuospatial function, attention, impulsivity, motivation/apathy, anxiety, social interaction and circadian rhythm at 3 and 5 months after Htt reduction. Reduction of Htt will be validated using an established mesoscale discovery assay and immunohistochemical analysis of the brain cytoarchitecture and cellular integrity will be undertaken. These data will be the first to explore the impact of lowering Htt in the adult brain on cognitive and neuropsychiatric function. Subsequent experiments will consider the direct interaction between wild-type Htt and mHtt. To achieve this, we will cross breed the novel CAG-Cre TAM-inducible Htt knockdown mouse model with an HD mouse model and assess the functional impact of knocking down Htt in this context on cognitive function and neuronal integrity.

This project will seek to address two key questions:

1. Does loss of function of wild-type Htt affect cognitive function in the adult brain?

2. Does the interaction between toxic mHtt gain-of-function and wild-type Htt loss-of-function affect cognitive function in the adult brain.

We are in an exciting era in which genetic modifying treatments for HD have entered into Phase I/II clinical trials. However, the results of Roche’s recent trial emphasise the need to more precisely understand the function of the gene/protein being manipulated and for better understanding of the impact of modulating Htt on cognitive function. 

*Please note that this project can be completed as an MPhil or PhD*

Candidate requirements

A 1st or Upper 2nd class UK honours degree or equivalent. Please visit School of Biosciences Postgraduate Research for more details.

For those whose first language is not English, IELTS with an overall score of 6.5 with 5.5 in all subskills, or equivalent. Please see our English Language Requirements guidance for more details.

How to Apply 

To submit a formal application via Cardiff University’s online application service, click the 'Institution Website' button on this advert; in the ‘Apply’ box at the top-right of the page, select Qualification (Doctor of Philosophy/Master of Philosophy), Mode of Study (Full Time) and Start Date (this can be flexible as it is a self-funded project). This will take you to the application portal.

Candidates must submit the following:

 • Supporting statement

 • CV

 • Qualification certificates

 • Proof of English language (if applicable) 

In the research proposal section of the application, specify the project title and supervisors of the project. In the funding section, specify that you will be self-funding. If you are applying for more than one Cardiff University project with the same entry intake, please note this in the research proposal section as the form only allows you to enter one title.


Funding Notes

There is no funding attached to this project, so students will need to source their own (tuition, bench fees if applicable, living fees if applicable).

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