"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.
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 developing high-throughput screening approaches to identify genes and small molecules that modulate C9orf72 and other FTD/ALS genes. 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. Characterise new C9orf72 modifier genes in flies, iPSC-neurons and mouse models.
2. Investigate new mechanisms by which the C9orf72 repeat expansion causes neurodegeneration.
3. Investigate potential new gene therapy approaches for C9orf72 and related disorders.
4.Utilise screening approaches to identify small molecules with therapeutic relevance for FTD/ALS.
3. Team members
Dr Alex Cammack (Postdoctoral Researcher)
Dr Georgina Starling (Postdoctoral Researcher)
Dr Paula Oliveira (Postdoctoral Researcher)
Dr Alla Mikheenko (Postdoctoral Researcher)
Paolo Marchi (Postdoctoral Researcher)
Mireia Carcolé (Senior Research Technician)
Yashica Gupta (Research Technician)
Cristina Marisol Castillo Bautista (Research Assistant)
Dr Martha Roberts (Research Fellow)
Alessia Fisher (Research Fellow)
Dr Jonas Mechterscheimer (Research Fellow)
Catherine Heffner (PhD Student)
Rachel Coneys (PhD Student)
Puja Mehta (PhD Student)
Dr Rubika Balendra (Clinical Student)
4. Collaborations
Within UK DRI:
- Prof Henrik Zetterberg, UK DRI at UCL
- Prof Jonathan Rohrer, UK DRI at UCL
- Dr Marc Busche, UK DRI at UCL
- Prof Caleb Webber, UK DRI at Cardiff
- Professor Siddharthan Chandran, UK DRI at Edinburgh
- Dr Bhuvaneish Selvaraj, UK DRI at Edinburgh
- Dr Sarah Mizielinska, UK DRI at King's
- Dr Marc-David Ruepp, UK DRI at King's
Beyond UK DRI:
- Prof Pietro Fratta, UCL
- Prof Michael Ward, NIH, USA
- Prof Elizabeth Fisher, UCL
- Dr Tom Cunningham, MRC Prion Unit at UCL
- Dr Jeremy Carlton, KCL
- Prof Linda Partridge, UCL
- Dr Teresa Niccoli, UCL
- ARUK UCL Drug Discovery Institute
5. Topics
Frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), human iPSC neurons, disease models, c9orf72
6. Techniques
Drosophila models, patient IPSC-neurons, mouse models, CRISPR/Cas13, Simoa ELISA biomarker assay for the polyGP DPR
7. Key publications
Wilson KM, Katona E, Glaria I, Carcolé M, Swift IJ, Sogorb-Esteve A, Heller C, Bouzigues A, Heslegrave AJ, Keshavan A, Knowles K, Patil S, Mohapatra S, Liu Y, Goyal J, Sanchez-Valle R, Laforce RJ, Synofzik M, Rowe JB, Finger E, Vandenberghe R, Butler CR, Gerhard A, Van Swieten JC, Seelaar H, Borroni B, Galimberti D, de Mendonça A, Masellis M, Tartaglia MC, Otto M, Graff C, Ducharme S, Schott JM, Malaspina A, Zetterberg H, Boyanapalli R, Rohrer JD, Isaacs AM; Genetic FTD Initiative (GENFI).J Neurol Neurosurg Psychiatry. 2022 Jul;93(7):761-771. doi: 10.1136/jnnp-2021-328710. Epub 2022 Apr 4.PMID: 35379698
Gittings LM, Boeynaems S, Lightwood D, Clargo A, Topia S, Nakayama L, Troakes C, Mann DMA, Gitler AD, Lashley T, Isaacs AM. Symmetric dimethylation of poly-GR correlates with disease duration in C9orf72 FTLD and ALS and reduces poly-GR phase separation and toxicity. Acta Neuropathol. 2020 Feb;139(2):407-410.
Moens TG, Niccoli T, Wilson KM, Atilano ML, Birsa N, Gittings LM, Holbling BV, Dyson M, Thoeng A, Neeves J, Glaria I, Yu L, Bussmann J, Storkebaum E, Pardo M, Choudhary JC, Fratta P, Partridge L, Isaacs AM. C9orf72 arginine-rich dipeptide proteins interact with ribosomal proteins in vivo to induce a toxic translational arrest that is rescued by eIF1A. Acta Neuropatholoigca 2019 Mar;137(3):487-500.
Clayton EL, Norona FE, Edgar JR, Milioto C, Soriano A, Jafar-nejad P, Rigo F, Collinge J, Isaacs AM. Frontotemporal dementia causing CHMP2B impairs endolysosomal traffic – rescue by TMEM106B knockdown. Brain. 2018 Dec 1;141(12):3428-3442.
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
Mizielinska S, Grönke S, Niccoli T, Ridler CE, Clayton EL, Devoy A, Moens T, Norona FE, Woollacott IO, Pietrzyk J, Cleverley K, Nicoll AJ, Pickering-Brown S, Dols J, Cabecinha M, Hendrich O, Fratta P, Fisher EM, Partridge L, Isaacs AM. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. 2014; 345:1192-1194.
