Dissecting macroglial-neuronal crosstalk in C9ORF72 Frontotemporal dementia/ amyotrophic lateral sclerosis

Lead Research Organisation: University of Edinburgh

Abstract

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Technical Summary

The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019.

To reduce dementias and related neurodegenerative disorders (NDD) to merely the consequence of genetic and biochemical dysfunction, invariably from a neuron-centric perspective, is to understate the highly evolved, dynamic and cellular connectedness nature of the human brain. Multiple lines of evidence from pathology, genetics, radiology and experimental systems implicate a central role for glia in (i) not only maintaining (and tuning) neuronal function in health but also, dependent on disease context, being (ii) injurious or (iii) neuroprotective1. Yet the role of macroglia (astrocytes, oligodendrocytes [OLG]) in NDD and ageing, the major risk factor for NDD, is grossly understudied. Dissecting the nature of cellular autonomy and the mechanism of macroglial-mediated influences on neuronal biology and function in health, ageing and NDD requires an integration of diverse experimental approaches. One powerful strategy is the use of human iPS technologies for in vitro as well as, following transplant, longitudinal in vivo study of human glial
chimeric mice. This programme will focus on the development and use of mutant (plus gene-corrected isogenic pairs) patient-derived C9orf72 human iPS cells to study NGVU interactions. C9orf72 hexanucleotide G4C2 repeat expansion is an excellent model for studying NGVU cross-talk in NDD because: (i) it is the major genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); (ii) it shares key biological pathways with other NDD; (iii) it underlies a clinical continuum of FTD/ALS with overlapping pathology; and (iv) there is strong evidence for macroglial involvement and non-cell autonomous neurotoxicity in disease pathogenesis