"I hope that we will deliver fundamental new understanding of the molecular causes of frontotemporal dementia and amyotrophic lateral sclerosis and translate these findings towards new therapies." Adrian Isaacs
UK DRI Group Leader
As part of his undergraduate studies Prof Adrian Isaacs spent one year working at the Mayo Clinic with John Hardy and Mike Hutton, where he was part of the team that discovered that mutations in MAPT gene cause frontotemporal dementia (FTD). Following completion of a PhD at Oxford University and post-doctoral studies at Harvard Medical School, Prof Isaacs established his own group at UCL. As part of this UK DRI research programme, Adrian is investigating the molecular and cellular mechanisms that lead to FTD and amyotrophic lateral sclerosis.
1. At a glance
Tackling dementia: from genes to therapy
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically distinct neurodegenerative diseases. But the discovery that they share a common cause – an expansion of a six-letter DNA sequence within the C9orf72 gene - is helping to revolutionize our understanding of the diseases.
Scientists are studying the biological impact of the faulty version of the C9orf72 gene to work out the mechanisms that lead to FTD and ALS. They theorise that the resulting protein may not function properly and/or be toxic to neurons. The gene is also known to be highly active in immune cells in the brain, however, little is known about its role in these cell types and how this may contribute to disease.
Prof Adrian Isaacs is investigating the underlying molecular mechanisms behind C9orf72-related FTD and ALS using a variety of experimental techniques and model systems. He is also studying its role in immune cells, in collaboration with UK DRI at UCL fellow Dr Soyon Hong, and exploring its relationship with other proteins implicated in neurodegenerative diseases. The ultimate goal is to develop innovative treatment strategies – such as novel gene therapies.
2. Scientific goals
An intronic GGGGCC repeat expansion in C9orf72 is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeats are translated by an unconventional mechanism termed repeat-associated non-ATG translation into five different dipeptide repeat proteins (DPRs). The team has previously shown that DPRs can be very damaging to neurons. They have now performed a large-scale modifier screen in fruit flies expressing GGGGCC repeats in adult neurons. They have identified several genes that improve the survival of these flies. These genes have not previously been implicated in C9orf72 FTD/ALS and so may represent completely novel pathways for rescuing C9orf72 repeat toxicity, and potentially other forms of neurodegeneration.
The team is now extending investigation of these genes using induced pluripotent stem cells (iPSCs) derived from people with the C9orf72 repeat expansion. They are also trying to decipher whether these genes can improve mouse models of C9orf72 repeat expansion and aim to determine if they are potential candidates for gene therapy.
Adrian’s group have also recently developed new 'knock-in' mouse models to investigate each of the individual DPRs. These knock-in mice provide a more accurate disease model because the level of the normal C9orf72 protein is also reduced - as is observed in human patients. There is increasing interest in whether loss of the normal function of C9orf72 contributes or sensitises to neurodegeneration. One reason for this is that C9orf72 is involved in endolysosomal function and is also expressed in immune cells. The team’s newly generated knock-in mice offer a unique opportunity to investigate these pathways and their contribution to disease.
Main objectives and research goals:
1. To generate humanised C9orf72 mice. Replacing mouse C9orf72 genomic locus from intron 1 to stop codon with human C9orf72 sequence.
2. To characterise the top genetic modifiers of C9orf72 repeat toxicity and develop a CRISPR/Cas13-based approach to reduce C9orf72 repeat RNA.
3. To characterise immune cell dysfunction in C9orf72 knockin mice. The model provides a unique opportunity to identify the role of DPRs under the physiological c9orf72 promoter.
4. To characterise the relationship between C9orf72 and TDP-43. Using human/mouse chimeras or human-mouse transplants.
3. Team members
Dr Katie Wilson (Postdoctoral Researcher)
Dr Carmelo Milioto (Postdoctoral Researcher)
Dr Magda Atilano (Postdoctoral Researcher)
Almudena Santos (Technician)
Demelza Smeeth (Technician)
Olivia Attrebi (Technician)
Eszter Katona (Technician)
Liam Kempthorne (PhD Student)
Benedikt Holbling (PhD Student)
Sally Salomonsson (PhD Student)
Catherine Heffner (PhD Student)
Ashling Giblin (PhD Student)
Within UK DRI:
- Prof Henrik Zetterberg, UK DRI at UCL
Beyond UK DRI:
- Prof Elizabeth Fisher, UCL
- Dr Tom Cunningham, MRC Harwell
Frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), human iPSC neurons, disease models, c9orf72
Drosophila models, patient IPSC-neurons, mouse models, CRISPR/Cas13, Simoa ELISA biomarker assay for the polyGP DPR
7. Key publications
Balendra R, Isaacs AM. C9orf72-mediated ALS and FTD: multiple pathways to disease. Nat Rev Neurol. 2018;14 (9):544-558.
Fratta P, Sivakumar P, Humphrey J, Lo K, Ricketts T, Oliveira H, Brito-Armas JM, Kalmar B, Ule A, Yu Y, Birsa N, Bodo C, Collins T, Conicella AE, Mejia Maza A, Marrero-Gagliardi A, Stewart M, Mianne J, Corrochano S, Emmett W, Codner G, Groves M, Fukumura R, Gondo Y, Lythgoe M, Pauws E, Peskett E, Stanier P, Teboul L, Hallegger M, Calvo A, Chiò A, Isaacs AM, Fawzi NL, Wang E, Housman DE, Baralle F, Greensmith L, Buratti E, Plagnol V, Fisher EM, Acevedo-Arozena A. Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis. EMBO J. 2018;37(11). pii: e98684.
Fratta P, Isaacs AM. The snowball effect of RNA binding protein dysfunction in amyotrophic lateral sclerosis. Brain. 2018 May 1;141(5):1236-1238.
Moens TG, Mizielinska S, Niccoli T, Mitchell JS, Thoeng A, Ridler CE, Grönke S, Esser J, Heslegrave A, Zetterberg H, Partridge L, Isaacs AM. Sense and antisense RNA are not toxic in Drosophila models of C9orf72-associated ALS/FTD. Acta Neuropathol. 2018;135(3):445-457.
Simone R, Balendra R, Moens TG, Preza E, Wilson KM, Heslegrave A, Woodling NS, Niccoli T, Gilbert-Jaramillo J, Abdelkarim S, Clayton EL, Clarke M, Konrad M, Nicoll AJ, Mitchell J, Calvo A, Chio A, Houlden H, Polke JM, Ismail MA, Stephens CE, Vo T, Farahat AA, Wilson WD, Boykin DW, Zetterberg H, Partridge L, Wray S, Parkinson G, Neidle S, Patani R, Fratta P, Isaacs AM. G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. EMBO Mol Med. 2018;10 (1):22-31