"Our lab aims to better understand the role of genomic instability accrual in neurodegenerative disease such as Huntington’s disease, ALS, Parkinson's or Ataxia telangiectasia towards finding new therapeutic opportunities." Gabriel Balmus
UK DRI Group Leader
Interested in the mechanisms controlling the maintenance of nuclear and mitochondrial genomes in mature neurons, Prof Gabriel Balmus joined the UK DRI at Cambridge in 2018. Obtaining his PhD in Molecular and Integrative Physiology in 2013 at Cornell University, USA, he went on to complete postdoctoral training at the Gurdon Institute at University of Cambridge and the Wellcome Trust Sanger Institute. As Group Leader, Gabriel brings his wealth of expertise to research genomic instability in neurodegenerative diseases.
1. At a glance
Protecting neurons from harm as we age
Over the course of our lifetime, the DNA inside our cells is under constant attack – either from dangerous metabolic by-products such as reactive oxygen species, or external factors. To counter this threat, our bodies have evolved elaborate tools that can spot and repair damaged DNA. However, when these systems go wrong, a build-up of genetic faults can occur and disastrous consequences follow, such as neuronal loss.
Most neurons – the building blocks of our central nervous system – are created early on in life and are never replaced. Our body needs to protect these cells from harm for the 80 or more years that we are alive – otherwise, this can lead to devastating conditions such as Huntington's, Alzheimer’s or Parkinson’s disease. Therefore, scientists are exploring how DNA damage and/or erroneous repair contributes to the loss of function and death of neurons, and the processes that help safeguard these brain cells as we age.
Prof Gabriel Balmus is developing a sophisticated new experimental system to identify genetic and environmental factors involved in DNA damage, neurodegeneration and ageing in neurons. He hopes this will uncover key biological targets that will lead to the development of effective new treatments that can help protect diseased neurons from degeneration.
2. Scientific goals
Genomic instability (GIN) is an important feature of neurodegeneration and a hallmark of neuronal ageing; if therapeutically averted, this could lead to prevention, delay or reversal of GIN-related neurodegenerative disease. Most mature neurons are end-state (non-replicative) cells that need to live for 80+ years and over this time require the ability to deal with exogenous and endogenous factors that create DNA lesions (DNA damage). In mature neurons, these lesions are counteracted by the DNA damage response (DDR) via mechanisms that are as yet unclear. It is proposed that failure to impede GIN formation and/or execute accurate DNA repair will cause expansion of nucleotide repeats, cell cycle re-entry, loss of synapses, chronic inflammation, premature senescence, aggregation of proteins or cell death - processes that would lead to the initiation of diverse neuropathology. Hence, accumulation of GIN throughout life represents one of the hallmarks of numerous neurodegenerative diseases including Huntington’s Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Parkinson’s Disease (PD) and Alzheimer’s Disease (AD).
Although GIN is likely to be a central player in neurodegeneration, either in specific pathologies or ageing, to date there is no comprehensive understanding of the cause-effect relationship nor are there any approved therapies to combat neurodegeneration via maintenance of genomic stability. Currently, a major obstacle is a lack of cellular models that can be used to study relevant neurodegenerative-related cellular states in human mature neurons. In terms of the GIN connection, this is mainly due to the fact that most of the DDR-related research has been done in replicative transformed cell lines, usually of mesenchymal/cancer origin or GIN unstable, non-isogenic induced pluripotent cell lines (iPS). However, studying the DDR in any cell type other than genomically stable human/mouse embryonic stem cells that can be used for the derivation of mature neurons can produce dangerous inaccuracies.
Main objectives and research goals:
The overall aim of this research programme is to identify genetic factors that can re-balance GIN-related neurodegeneration in mature neurons and understand how these molecular processes contribute to neurodegenerative disease such as HD, ALS, PD or AD, as well as ageing. The specific aims are:
1. To study GIN-related neurodegeneration, develop relevant experimental disease models in both mouse and human isogenic ESCs that can be rapidly differentiated into neurons (iN) and/or organoids.
2. Using CRISPR-Cas9 and/or chemical mutagenesis to screen for factors that can rescue neurodegeneration upon increased endogenous (i.e. reactive oxygen species) damage in WT and selected disease backgrounds such as HD, ALS or PD.
3. Once modifiers are identified in screens or based on hypothesis driven research, understand the molecular mechanisms basis for re-balancing disease towards designing new drugs or re-purposing already available therapies.
4. Validate the relevant diagnostic and therapeutic targets and/or compounds in patient iPS and organoids as well as subsequent in vivo studies.
3. Team members
Matthew Ellis (Research Associate)
Michael Woods (Senior Technician)
Osama Bin Faisel (Technician)
Nadia Karimpour (Technician)
Berfin Barlas (Research Assistant)
James Shonhard (Research Assistant)
Jose Vicente (Research Assistant)
Ioana-Violeta (Research Assistant)
Mihai Miclaus (Research Assistant)
Andrei-Stefan Lia (Research Assistant)
Catalin Coltau (Research Assistant)
Irina-Maria Ungureanu (Research Assistant)
Annabel Curle (PhD Student)
Kyra Ungerleider (PhD Student)
Grace Zhao (PhD Student)
Rizwan Ansari (PhD Student)
Samuel Dolean (PhD Student)
Niko Aslanichvili (Masters Student)
Kangning He (Masters Student)
4. Collaborations
Within UK DRI:
- Dr Emmanouil Metzakoipian, UK DRI at Cambridge
- Prof Giovanna Mallucci, UK DRI at Cambridge
- Prof David Rubinsztein, UK DRI at Cambridge
- Prof Sarah Tabrizi, UK DRI at UCL
Beyond UK DRI:
- Prof Josef Penninger, Institute of Molecular Biotechnology in Austria
- Dr Andras Lakatos, University of Cambridge
- Prof Simon David, Harvard University, USA
5. Topics
Nucleotide expansion repeats, genomic instability (GIN), DNA damage response (DDR), Huntington's Disease, Parkinson's Disease, ALS
6. Techniques
Human/mouse haploid ESCs, transdifferentiation, iN system, conditional protein-degron systems (SMASH-tag), CRISPR-Cas9 screening, EMS point mutagenesis
7. Key publications
Elling U, Woods M, Doe B, Fu B, Yang F, Ling Ng B, Forment J, Adams DJ, Jackson SP, Penninger JM and Balmus G. Derivation and maintenance of mouse haploid embryonic stem cells – Nature protocols 2019; 14, 1991
G Balmus, JV Forment, D Pilger, J Coates, M Demir, M Sczaniecka-Clift, A Barros, M Woods, B Fu, F Yang, E Chen, C Oldreive, T Stankovic, H Ponstingl, M Herzog, K Yousa, M Garnett, DJ Adams, A Bradley, E Metzakopian, SP Jackson. ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks. Nature Communications 2019; 10(1):87.
Balmus, G., Larrieu, D., Barros, A.C., Collins, C., Abrudan, M., Demir, M., Geisler, N.J., Lelliott, C.J., White, J.K., Karp, N.A. and Atkinson, J., 2018. Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome. Nature communications, 9(1), p.1700.
Balmus, G., Barros, A.C., Wijnhoven, P.W., Lescale, C., Hasse, H.L., Boroviak, K., Le Sage, C., Doe, B., Speak, A.O., Galli, A. and Jacobsen, M., 2016. Synthetic lethality between PAXX and XLF in mammalian development. Genes & development, 30(19), pp.2152-2157.
Balmus, G., Karp, N.A., Ng, B.L., Jackson, S.P., Adams, D.J. and McIntyre, R.E., 2015. A high-throughput in vivo micronucleus assay for genome instability screening in mice. Nature protocols, 10(1), p.205.
Balmus, G., Zhu, M., Mukherjee, S., Lyndaker, A.M., Hume, K.R., Lee, J., Riccio, M.L., Reeves, A.P., Sutter, N.B., Noden, D.M. and Peters, R.M., 2012. Disease severity in a mouse model of ataxia telangiectasia is modulated by the DNA damage checkpoint gene Hus1. Human molecular genetics, 21(15), pp.3408-3420.
