UCL Queen Square Institute of Neurology


Basic science research

Bates Lab

The research of the Bates lab is focused on understanding the molecular basis of Huntington’s disease (HD) and developing therapeutic interventions. Toward this aim, we work closely with the research group of Professor Tabrizi, within the Huntington’s Disease Research Centre. Huntington’s disease is a devastating inherited neurodegenerative disorder that affects movement and cognition and is ultimately fatal.

The mutation that causes Huntington’s disease is the expansion of a CAG repeat in the huntingtin (HTT) gene that leads to an abnormally long polyglutamine tract in the huntingtin protein (HTT). We are particularly interested in the direct effect of the mutation on HTT expression. We have found that the presence of the mutation results in the incomplete splicing of HTT resulting in the production of a small mRNA that encodes an exon 1 HTT protein. Exon 1 HTT has been shown to be highly pathogenic in a wide range of model systems. One programme of our research is directed toward understanding the molecular basis of the incomplete splicing event and determining the extent to which exon 1 HTT contributes to disease pathogenesis. We are conducting a preclinical assessment of approaches by which the generation of this small mRNA species could be prevented.

We use genetic and pharmacological approaches to validate therapeutic targets in mouse models of Huntington’s disease and over the past 10 years, have published a number of in vivo experiments which indicate that Huntington’s disease is caused by an aggregated, and not a soluble, form of the HTT protein. We are specifically interested in targeting the early stages of HTT aggregation, however, very little is known about the structure of the seeding competent aggregates that form in vivo. We are currently working with Prof. Erich Wanker (Berlin) and Dr. Gabriele Kaminski Schierle (Cambridge) to better understand the seeding and aggregation process.

Tabrizi Lab

Huntington’s disease
Huntington's disease is caused by an abnormal expansion of a sequence of three DNA bases, or building blocks (CAG), within the HTT gene. In healthy people, the CAG is repeated 10 to 35 times in a row, whereas people with the disease have 36-120+ repeats. This expanded sequence is inherently unstable and tends to get longer over time, causing the death of neurons – particularly within the brain tissues that are most vulnerable to the disease.
People with longer CAG expansions tend to develop symptoms at an earlier age – and their disease is likely to progress more quickly. However, this isn’t clear-cut and other genes elsewhere in a person’s genome can also influence age of disease onset. We are now starting to identify these so-called ‘modifying genes’ – and some are involved in repairing faults in our DNA.
The Tabrizi lab are aiming to build our understanding of how DNA repair mechanisms are involved in modifying the development of Huntington’s disease. We hope to use this knowledge to develop novel therapeutic approaches that could stop, slow down or reverse the progression of the disease. We have already tested one potential new therapy in an early-stage clinical trial in people with dementia, with encouraging results.

Scientific goals
The DNA damage response (DDR) is a series of overlapping pathways that sense and repair the DNA damage that occurs continually throughout our lives. Defects in components of this DDR system result in neurodegeneration, such as ataxia telangiectasia, xeroderma pigmentosum, ataxia with oculomotor apraxia-1 (AOA1) and spinocerebellar ataxia with axonal neuropathy (SCAN1), suggesting the nervous system is especially sensitive to DNA damage.
In Huntington’s disease (HD) the expanded CAG repeat is inherently unstable, tending to increase in length in a time-dependent and tissue-specific manner, in a process known as somatic instability. There is prominent expansion in the striatum, the tissue most vulnerable to the disease, but relative stability in the cerebellum, which is unaffected. Expansion produces an increasingly toxic protein and is correlated with earlier age at onset and increasingly severe disease, suggesting it is a key mechanism underlying the tissue-specific neurodegeneration seen in HD.
In HD patients, onset varies by several decades in people with the same CAG repeat length in blood, and around 50% of this variability is heritable, demonstrating the existence of genetic modifiers elsewhere in the genome. The DNA damage response has been implicated as a modifier of CAG instability, with knockout or variation of DNA mismatch repair (MMR) components MutSβ (MSH2/MSH3), MutLα (MLH1/PMS2) or MutLγ (MLH1/MLH3) significantly reducing somatic expansion and improving disease phenotype in HD mice. 
Genome-wide association studies (GWAS) studies have identified the DNA interstrand crosslink repair nuclease FAN1, the DNA mismatch detector complex MutSβ, nuclease complexes MutLα and MutLγ, and ligase LIG1, as modifiers of somatic instability, HD onset and progression.
Interventions harnessing these DNA repair mechanisms could have the potential to modify the disease course. One of the greatest challenges in the field is to understand how these DNA repair mechanisms maintain genomic stability, whilst also contributing to cell degeneration in HD.

High Content Screening
This research focuses on using a high throughput screening platform to characterise and examine phenotypes in pluripotent stem cell derived neurons. High content imaging allows for unbiased experimental observation and rapid acquisition of large volumes of data. We are currently investigating the role of mutant huntingtin in nuclear cytoplasmic transport and whether defects observed can be alleviated using antisense oligonucleotides (ASOs) in collaboration with Takeda Pharmaceuticals.

Team Wild

Team Wild undertakes research using human volunteers, to make discoveries and therapeutic advances in Huntington’s disease. Our particular focus is biomarkers – substances that can be measured in body fluids like blood or cerebrospinal fluid, that can tell us something useful about how Huntington’s affects the brain and body. 

In 2015 we led the development and testing of the first technique to accurately measure the amount of mutant huntingtin in cerebrospinal fluid. Mutant huntingtin is the abnormal protein that causes Huntington’s, and cerebrospinal fluid is a clear liquid produced by the brain, that bathes and supports the nervous system. This measurement technique is now being used as a biomarker in multiple trials of new treatments to lower the production of the mutant huntingtin. It was used to show in 2017 that the huntingtin-lowering drug HTTRx/RG6042 successfully lowered huntingtin production for the first time in Huntington’s patients.

Professor Wild has been involved in huntingtin-lowering programs since 2014 and was a senior investigator on the first-in-human trial of HTTRx. He is the global chief investigator of the Roche Gen-PEAK trial, studying the pharmacokinetics and pharmacodynamics of RG6042.

Team Wild has pioneered the study of cerebrospinal fluid as a means of understanding Huntington’s disease in patients. Our HD-CSF study, funded by the Medical Research Council, was the first longitudinal study of cerebrospinal fluid with advanced magnetic resonance imaging.

We have led the development of neurofilament light protein as a biomarker in Huntington’s disease. In 2017 we showed that this protein, which is released from damaged neurons, could be detected at increased levels in the blood of Huntington’s disease mutation carriers many years before symptoms begin, and that the level predicts onset, progression and the rate of brain atrophy. In 2018 we measured neurofilament light and mutant huntingtin in parallel in cerebrospinal fluid and showed that neurofilament was the better predictor of disease severity. 

Professor Wild is the Global Chief Investigator of the HDClarity study, the first multi-national cerebrospinal fluid collection initiative in Huntington’s disease. HDClarity is funded by CHDI Foundation and samples and data are available for any researcher to study Huntington’s disease.

Our current focus is advanced studies in cerebrospinal fluid to understand the events leading to neurodegeneration in the brains of Huntington’s disease mutation carriers.

We collaborate widely with academic, industry and foundation researchers from across the globe to understand HD in patients and advance the development of new treatments.

Please see our People page for further information on our teams.