"We aim to understand the mechanisms that cause, and the relationship between, somatic instability of the CAG repeat mutation, incomplete splicing of the huntingtin mRNA and aggregation of the huntingtin protein. We are assessing the effect that therapeutic approaches to lower huntingtin RNA and protein levels have on these events and downstream phenotypes." Gillian Bates
UK DRI Group Leader
Prof Gillian Bates has been at the forefront of Huntington’s disease research for many years, receiving the GlaxoSmithKline prize for co-discovery of disease cause in 1998 and co-founding the Huntington’s Disease Centre at UCL. She was involved in the first cloning of the Huntington's gene and developed the first mouse model of the condition. Gill has also been elected a fellow of the Academy of Medical Sciences, a member of the European Molecular Biology Organisation and a Fellow of the Royal Society.
1. At a glance
Developing sophisticated new treatments for Huntington’s disease
Huntington's disease is a devastating inherited neurodegenerative condition affecting movement, learning, thinking and emotions. People usually begin to develop symptoms in their 30s or 40s and get progressively worse – sadly, there is no cure.
The disease is caused by a fault within the huntingtin gene, which provides instructions for making a protein called huntingtin. In healthy people, a repeated sequence of three DNA building blocks (CAG) occurs 6 to 35 times in the gene, whereas people with the faulty version have from 36 to more than 120 CAGs. A longer CAG repeat is correlated with earlier age of onset and faster disease progression.
Prof Gill Bates is aiming to understand the molecular basis of Huntington’s disease in order to develop innovative new treatments. In particular, her team are focussing on ways to lower the levels of abnormal huntingtin molecules in cells. They are also developing ways to target DNA repair genes, thought to be involved in the disease, and studying the build-up of abnormal huntingtin protein aggregates inside the brain. The team will assess the effectiveness of any potential new treatments in laboratory models.
2. Scientific goals
Huntington’s disease (HD) is caused by a trinucleotide CAG repeat expansion, for which (CAG)40 and above are fully penetrant gain-of-function mutations. Overall, larger CAG repeat expansions are associated with an earlier age of onset for the disease. The CAG repeat is unstable on gametic transmission, with large expansions occurring when the mutation is transmitted from the father, with the consequence that most juvenile cases are paternally inherited. It is also unstable in somatic tissues, which in HD mouse models has a characteristic pattern of instability in brain regions and peripheral tissues, and in the brain occurs in differentiated post-mitotic neurons. Large CAG repeat expansions also occur in HD patient brains, with larger expansions occurring in neurons rather than in non-neuronal cells.
It has been known for many years, that the ablation of specific components of the mismatch repair pathway in mouse models, e.g. Msh2, Msh3, Mlh1, completely stabilises the CAG repeat in somatic tissues. Many genes in the mismatch repair and other DNA repair pathways have now been identified as genetic modifiers of the age of onset and/or disease progression in GWAS studies.
The HD gene has 67 exons and the CAG repeat mutation is within the coding region of exon 1. The gene is translated into a 350 kDa protein (HTT). The team has found that exon 1 of the huntingtin gene (HTT) does not always splice to exon 2, resulting in the production of a small polyadenylated exon 1–intron 1 transcript that is translated into an exon 1 HTT protein. Therefore, there are two main HTT transcripts and the level of incomplete splicing increases with increasing CAG repeat length in both knock-in mouse models and HD patient brains. The exon 1 HTT protein is aggregation-prone and highly pathogenic.
This programme aims to understand the molecular basis of HD and validate therapeutic targets for HD. The current focus is to understand the events that underlie: the somatic instability of the CAG repeat mutation, the incomplete splicing of HTT that generates a small transcript encoding the pathogenic exon 1 HTT protein, and the in vivo consequences of HTT aggregation.
Main objectives and research goals:
1. To understand the extent to which the exon 1 HTT protein contributes to pathogenesis and to develop therapeutic strategies to decrease its levels. Using a combination of genetics and HTT lowering agents in knock-in HD mouse models.
2. To explore DNA repair and somatic expansion as a therapeutic target. Developing reagents that target MSH3 and performing the preclinical assessment of these in mice.
3. Team members
Rachel Flomen (Project Manager)
Dr Sarah Aldous (Postdoctoral Researcher)
Dr Marie Bondulich (Postdoctoral Researcher)
Dr Casandra Gomez-Paredes (Postdoctoral Researcher)
Dr Christian Landles (Postdoctoral Researcher)
Dr Pamela Farshim (Postdoctoral Researcher)
Dr Sandra Fienko (Postdoctoral Researcher)
Dr Aikaterini Papadopoulou (Postdoctoral Researcher)
Dr Kirupa Sathasivam (Postdoctoral Researcher)
Dr Ed Smith (Postdoctoral Researcher)
Nadira Ali (Research Assistant)
Maria Canibano Pico (Research Assistant)
Arzo Iqbal (Research Assistant)
Iulia Nita (Research Assistant)
Georgina Osborne (Research Assistant)
Jemima Phillips (Research Assistant)
Within UK DRI:
- Prof Paul Whiting, UK DRI at UCL – screening for a small molecule that facilitates HTT exon 1–exon 2 splicing.
- Prof Sarah Tabrizi, UK DRI at UCL – developing reagents that target MSH3 and performing the preclinical assessment of these potential therapeutic strategies in mice.
- Prof Henrik Zetterberg, UK DRI at UCL – development of sensitive assays to measure HTT proteins in cell systems and biofluids.
- Prof Karen Duff – the direct conversion of fibroblasts to neurons.
Beyond UK DRI:
- Prof Helen Saibil, Birkbeck College – establishing correlative light and electron microscopy (CLEM) with tomography on tissues from HD mouse models.
- Prof Erich Wanker, Max Delbruck Institute, Berlin – HTT aggregation.
- Dr Frank Bennett, Ionis Pharmaceuticals – developing antisense oligonucleotides targeting the small exon 1 HTT transcript.
- Prof Anastasia Khvorova, University of Massachusetts – developing siRNAs modified to distribute throughout the brain.
- Dr. Andreas Neueder, University of Ulm – RNAseq and long-range RNA sequencing
Huntington’s disease, CAG repeat, mouse models, incomplete splicing, HTT aggregation
Transgenic mouse models, minigene screening assay, qPCR, TR-FRET, MSD, AlphaLISA, Singulex, correlative light and electron microscopy (CLEM)
7. Key publications
Fienko S, Landles C, Sathasivam K, McAteer SJ, Milton RE, Osborne GF, Smith EJ, Jones ST, Bondulich MK, Danby ECE, Phillip J, Taxy BA, Kordasiewicz HB, Bates GP (2022) Alternative processing of human HTT mRNA with implications for Huntington’s disease therapeutics. Brain in press.
Zhou Y, Peskett TR, Landles C, Warner JB, Sathasivam K, Smith EJ, Chen S, Wetzel R, Lashuel HA, Bates GP, Saibil HR (2021) Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington’s disease. Acta Neuropathologica Comm., 9, 70. doi.org/10.1186/s40478-021-01172-z.
Smith EJ, Farshim PP, Flomen R, Jones ST, McAteer SJ, Deverman BE, Gradinaru V, Bates GP (2021) Use of high-content imaging to quantify transduction of AAV-PHP viruses in brain following systemic delivery. Brain Comm., 3, fcab105. doi:10.1093/braincomms/fcaa231.
Landles C, Milton RE, Jean A, McLarnon S, McAteer SJ, Taxy BA, Osborne GF, Zhang C, Duan W, Howland D, Bates GP (2021) Development of novel bioassays to detect soluble and aggregated huntingtin proteins on three technology platforms. Brain Comm. 3, fcaa231. doi.org/10.1093/braincomms/fcaa231.
Landles C, Milton RE, Ali N, Flomen R, Flower M, Schindler F, Gomez-Paredes C, Bondulich MK, Osborne GF, Goodwin D, Salsbury G, Benn CL, Sathasivam K, Edward J. Smith1, Tabrizi SJ, Wanker EE, Bates GP (2020) Subcellular localisation and formation of huntingtin aggregates correlates with symptom onset and progression in a Huntington’s disease model. Brain Communications, 2, fcaa066. Doi: 10.1093/braincomms/fcaa066.
Neueder A, Dumas AA, Benjamin AC, Bates GP (2018) Regulatory mechanisms of incomplete HTT mRNA splicing in Huntington’s Disease. Nat. Comm. 9: 3955. doi.org/10.1038/s41467-018-06281-3
Neueder A, Landles C, Ghosh R, Howland D, Myers RH, Faull RLM, Tabrizi SJ, Bates GP (2017) The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients. Scientific Reports, 7: 1307 | DOI:10.1038/s41598-017-01510-z
Sathasivam K*, Neueder A*, Gipson TA, Landles C, Benjamin AC, Bondulich MK, Smith DL, Faull RLM, Roos RAC, Howland D, Detloff PJ, Housman DE, Bates GP (2013). Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington’s disease. Proc. Natl. Acad. Sci. 110, 2366-2370. doi: 10.1073/pnas.1221891110