"Our human centred discovery research that leverages the cohort and data strengths of the UK along with application of new experimental technologies will, we hope, begin to unravel the mysteries of dementias and related neurodegenerative disorders." Siddharthan Chandran
UK DRI Group Leader
An expert in regenerative neurology, Prof Siddharthan Chandran is Director of the Centre for Clinical Brain Sciences, Edinburgh Neuroscience, the Euan MacDonald Centre and the Anne Rowling Regenerative Neurology Clinic in Edinburgh. Siddharthan bridges the gap between clinic and the lab, having trained at Southampton and UCL before obtaining a PhD in developmental neurobiology from the University of Cambridge in 2000. He was elected a Fellow of The Royal Society of Edinburgh in 2018, and joins the UK DRI at Edinburgh to lead an exciting programme of research investigating the genetics of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
1. At a glance
Dissecting a genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)
Amyotrophic lateral sclerosis (ALS, also known as motor neurone disease (MND)) and frontotemporal dementia (FTD) are neurodegenerative diseases, which emerging evidence shows may have significant overlap in biological cause. Although most people who develop ALS have no family history of the disease, around 5-10% of cases are inherited – with up to 40% due to a fault in a gene known as C9orf72. This faulty gene is also the most common genetic cause of FTD.
In healthy individuals, the DNA sequence of C9orf72 contains a short recurring repeat of 6-letters. But in people with a faulty copy, this is hugely expanded and leads to accumulation of abnormal proteins. Prof Siddharthan Chandran is studying the biological consequences of these so-called ‘repeat expansions’ in the C9orf72 gene on different types of brain cell, particularly immune cells that support neurons.
Siddharthan’s aim is to tease out the root causes of ALS and/or FTD and identify ways to help protect neurons from damage. For example, he will explore if an accumulation of the mutant gene sequence within cells is toxic, or alternatively, if problems arise due to low levels of the functional C9orf72 protein. He hopes this work will lead to effective new treatments in the future.
2. Scientific goals
The overall objective of this UK DRI programme, led by Prof Siddharthan Chandran, is to better understand glial-neuronal cross talk and how this is altered in neurodegenerative disorders, using patient-derived mutant C9orf72 iPS cell lines as a prototypic example, and determining whether manipulating axo-glial interaction is neuroprotective.
The C9orf72 mutation (mC9) is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How repeat expansions in the C9orf72 gene (C9) cause these conditions is unknown. Three broad mechanisms, not mutually incompatible, are offered: loss of function of C9 protein, gain of function toxicity via C9 repeat RNA foci or dipeptide repeats (DPRs) generated by non-ATG translation of repeats. Numerous cellular processes, many also found in both sporadic and familial ALS/FTD, have been identified. Any unifying mechanism will need to also account for the finding of mis-accumulation of insoluble TDP-43, an RNA-binding protein, in >97% of ALS cases.
Until recently, a neurocentric approach has dominated the study of neurodegenerative disease, including ALS/FTD, and yet multiple lines of evidence show glia pathology including accumulation of TDP-43 and C9 RNA foci in ALS. This programme’s focus is on defining the molecular, cellular and functional cell and non-cell autonomous consequences of mC9 mutation on glia.
The team’s approach combines in vitro and in vivo (chimeric transplants) experiments using 3 independent mutant patient iPS cell lines plus isogenic gene-corrected pair to derive neurons (cortical and MN), astrocyte, oligodendrocyte and microglia. Current studies remain focused on first confirming and defining key phenotypes, with follow up mechanistic experiments guided by unbiased approaches such as transcriptomics and proteomics.
Main aims and research goals:
1. To determine cell autonomous consequences of C9orf72 mutation on cortical and motor neurons. The team are systematically mapping the cellular and biochemical pathology of cortical and motor neurons – to identify unique and overlapping transcriptomal neuronal signatures and discover regulatory processes that potentially interact with glia signalling pathways.
2. To determine the molecular, cellular and functional cell and non-cell autonomous consequences of C9orf72 mutation on cortical and spinal astrocytes. The team are defining the kinetics and identity of astrocyte-mediated factors that result in non-cell autonomous neuronal pathophysiology – they are examining the in vivo impact of age and mutant astrocytes on neuronal health using chimeric transplant experiments.
3. To determine the molecular, cellular and functional cell and non-cell autonomous consequences of C9orf72 mutation on cortical and spinal oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLGs). The team are defining the kinetics and identity of OLG mediated factors that result in non-cell autonomous neuronal pathophysiology – using transplant experiments to evaluate myelination efficiency and the in vivo impact of age and mutant OLGs on neuronal health.
3. Team members
Dr Karen Burr (Project Officer)
Dr David Hampton (Academic)
Dr Poulomi Banerjee (Postdoctoral Researcher)
Dr Roderick Carter (Postdoctoral Researcher)
Dr Marcus Keatinge (Postdoctoral Researcher)
Dr Vidya Ramesh (Postdoctoral Researcher)
Dr Arpan Mehta (Postdoctoral Researcher)
Dr Nhan Pham (Postdoctoral Researcher)
Dr Paul Baxter (Postdoctoral Researcher)
Rebecca Hughes (Data Scientist)
Dr Raja Nirujogi (Visiting Scientist)
Denise O'Keefe (Senior Technician)
James Cooper (Senior Technician)
Karen Gladstone (Senior Technician)
Jyoti Nanda (Senior Technician)
David Story (Senior Technician - Lab manager)
Kim Morris (Technician - jointly with Prof Josef Priller)
Dr Maria Stavrou (PhD Student)
Steph Panol (PA)
Within UK DRI:
- Prof Giles Hardingham, UK DRI at Edinburgh
- Prof Chris Shaw, UK DRI at King's
- Prof Tara Spires-Jones, UK DRI at Edinburgh
- Prof Dario Alessi, UK DRI Associate Member, MRC PPU, University of Dundee
- Prof Josef Priller, UK DRI at Edinburgh
- Prof Adrian Isaacs UK DRI at UCL
Beyond UK DRI:
- Prof Colin Smith, University of Edinburgh
- Prof Phillip Van Damme, VIB-KU Leuven
- Prof Steven Goldman, University of Rochester Medical Center
- Prof Gareth Miles, University of St. Andrews
- Dr Matthew Livesey, University of Sheffield
- Dr Thimo Kurz, University of Glasgow
C9orf72 gene, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), triplet repeat expansions, glial cells
Transcriptomics, proteomics, chimeric transplants, iPSC models, RNA-seq
7. Key publications
Banerjee P, Mehta AR, Nirujogi RS, Cooper J, James OG, Nanda J, Longden J, Burr K, McDade K, Salzinger A, Paza E, Newton J, Story D, Pal S, Smith C, Alessi DR, Selvaraj BT, Priller J, Chandran S. Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration. Sci Adv. 2023 Apr 21;9(16):eabq0651. doi: 10.1126/sciadv.abq0651.
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Mehta AR, Gregory JM, Dando O, Carter RN, Burr K, Nanda J, Story D, McDade K, Smith C, Morton NM, Mahad DJ, Hardingham GE, Chandran S*, Selvaraj BT* (2021) Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis. Acta Neuropathologica. doi:10.1007/s00401-020-02252-5
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James OG, Selvaraj BT, Magnani D, Burr K, Connick P, Barton SK, Vasistha NA, Hampton DW, Story D, Smigiel R, Ploski R, Brophy PJ, Ffrench-Constant C, Lyons DA, Chandran S. iPSC-derived myelinoids to study myelin biology of humans. Dev Cell. 2021 May 3;56(9):1346-1358.e6. doi: 10.1016/j.devcel.2021.04.006. PMID: 33945785; PMCID: PMC8098746.
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Perkins EM*, Burr K*, Banerjee P, Mehta AR, Dando O, Selvaraj BT, Suminaite D, Nanda J, Henstridge CM, Gillingwater TH, Hardingham GE, Wyllie DJA, Chandran S*, Livesey MR*. Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction. Mol Neurodegener. 2021 Mar 4;16(1):13. doi: 10.1186/s13024-021-00433-8. PMID: 33663561; PMCID: PMC7931347.
Fumagalli L*, Young FL*, Boeynaems S*, De Decker M, Mehta AR, Swijsen A, Fazal R, Guo W, Moisse M, Beckers J, Dedeene L, Selvaraj BT, Vandoorne T, Madan V, van Blitterswijk M, Raitcheva D, McCampbell A, Poesen K, Gitler AD, Koch P, Berghe PV, Thal DR, Verfaillie C, Chandran S, Van Den Bosch L, Bullock SL*, Van Damme P* (2021) C9orf72-derived arginine-containing dipeptide repeats associate with axonal transport machinery and impede microtubule-based motility. Science Advances 7 (15):eabg3013. doi:10.1126/sciadv.abg3013
Zhao C, Devlin AC, Chouhan AK, Selvaraj BT, Stavrou M, Burr K, Brivio V, He X, Mehta AR, Story D, Shaw CE, Dando O, Hardingham GE, Miles GB, Chandran S. Mutant C9orf72 human iPSC-derived astrocytes cause non-cell autonomous motor neuron pathophysiology. Glia. 2020 May;68(5):1046-1064. doi: 10.1002/glia.23761
Chataway J, De Angelis F, Connick P, Parker RA, Plantone D, Doshi A, John N, Stutters J, MacManus D, Prados Carrasco F, Barkhof F, Ourselin S, Braisher M, Ross M, Cranswick G, Pavitt SH, Giovannoni G, Gandini Wheeler-Kingshott CA, Hawkins C, Sharrack B, Bastow R, Weir CJ, Stallard N, Chandran S; MS-SMART Investigators. Efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis (MS-SMART): a phase 2b, multiarm, double-blind, randomised placebo-controlled trial. Lancet Neurol. 2020 Mar;19(3):214-225. doi: 10.1016/S1474-4422(19)30485-5
Vasistha NA, Johnstone M, Barton SK, Mayerl SE, Selvaraj B T, Thomson PA, Dando O, Grünewald E, Alloza C, Bastin ME, Livesey MR, Economides K, Magnani D, Makedonopolou P, Burr K, Story DJ, Blackwood DHR, Wyllie DJA, McIntosh AM, Millar JK, Ffrench-Constant C, Hardingham GE, Lawrie SM, Chandran S. Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction. Mol Psychiatry. 2019 Nov;24(11):1641-1654. doi: 10.1038/s41380-019-0505-2.
Selvaraj, B.T., Livesey, M.R., Zhao, C., James, O.T., Gregory, J., Cleary, E.M., Perkins, E.M., Lillico, S.G., Lee, Y-B., Nishimura, A.L., Vasistha, N.A., Magnani, D., Barooah, S., Burr, K., Story, S., Shaw, C.E., Kind, P.C., Whitelaw, B.A., Wilmut, I., Hardingham, G.E., Wyllie, D.J.A., and Chandran, S. C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+ -permeable AMPA receptor-mediated excitotoxicity. Nature Communications 2018; 9(1) 347