Can early intervention with astrocytes delay the progression of Huntington's disease?
Application deadline: 23 November 2018
Start date: October 2019
Research theme: Neuroscience and Mental Health
Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an abnormally long CAG repeat sequence in exon 1 of the Huntingtin (Htt) gene. The burden of pathology is in the striatum where medium spiny projection neurons (MSNs) are selectively lost. Transplantation of immature striatal cells derived from developing fetal striatum (ganglionic eminence: GE) improves function in animal studies, and proof of principle exists that transplantation of similar cells can modify symptoms in people with HD (Reference 1).
Several groups, including ours, seek to differentiate donor cells from pluripotent stem cells, rather than fetal cells, and to date, the focus has been on generating MSNs. However, there is evidence that astrocytes are also affected in HD:
- fibrillary astrocytosis and loss of glia GLT1 in the striatum are early features of HD (glutamatergic damage is a key pathogenic process in HD and GLT1 allows its reuptake (Reference 2);
- transplantation of mutant Htt-transfected astrocytes into normal neonatal mice produces an HD-like pathology (Reference 2);
- transplantation of normal human fetal astrocytes into neonatal transgenic HD mice improves behaviour and MSN physiology (Reference 3).
These studies suggest that astrocytes are an important component of neural grafts, and may even serve as a therapeutic in their own right. However, studies to date have used transplants of human astrocytes into the neonatal rodent brain (neonatal xenografts), whereas a potential human therapeutic would require transplantation of human cells into the human adult brain (adult allograft).
Project aims and method
We will test the hypothesis that astrocyte transplants can improve function in an adult HD mouse model, thereby taking the first steps towards exploring astrocyte transplants as a potential therapy for HD. You will test the ability of mouse (allograft) or human (xenograft) astrocytes to improve function in HD transgenic mouse models.
You will also compare astrocyte-only grafts to neural (mixed astrocyte and neuron) grafts to explore the extent to which astrocytes are important for recovery in neural grafts in HD mouse models. Astrocytes will be derived from fetal GE as in3 (ethically sourced human fetal cells are available in Cardiff through the SWIFT project). The Q111 HD transgenics line (cyclosporine treated) will be used as the host, as disease onset is around 4-6 months, allowing transplantation in the early disease phase, and it has been fully phenotyped in Cardiff.
Outcomes will include:
- Behavioural assessments (hand testing and operant box testing in Cardiff);
- striatal physiology, including whole patch clamp recording from striatal slices to test the effect of grafts on MSN hyperexcitability and integration into synaptic networks;
- two-photon imaging to test astrocyte function (Exeter), and histology including mutant Htt inclusions (Cardiff).
- Dunnett et al Neurobiol Dis 2014 61:79-89
- Faideau et al Hum Mol Genet 2010 1;19:3053-6
- Benraiss et al Nat Commun 2016 7;7:11758
Prof Andrew Randall, University of Exeter.
Dr Jon Brown, University of Exeter.