A17 Glial-specific transcriptomic changes in HD

Abstract

Huntington’s disease (HD) is a severely debilitating, autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing of human post mortem brain in 4 regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from HD patients and age and sex matched controls, we found an altered heterogeneity of glia in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight two possible mechanisms that characterise the glial contribution to disease pathology. Firstly, we show that upregulation of chaperone-mediated protein folding represents a cross-glial signature in HD, which likely reflects an adaptive response to the accumulation of toxic Huntingtin protein and might promote cell survival. Secondly, we show an oligodendrocyte-specific upregulation of the calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1A (PDE1A) in HD compared to controls, which could cause dysfunction to key cellular functions due to the downregulation of the important second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our results support the hypothesis that glia have an independent role in the pathology of HD, showing that all types of glia are affected in the disease. As glia are more tractable than neurons our findings may be of therapeutic relevance.

Authors 9

1. Sunniva M. K. Bøstrand

   MRC Centre for Regenerative Medicine · University of Edinburgh

   Affiliation as printed

   University of Edinburgh, Centre for Regenerative Medicine, Edinburgh, UK

2. Luise A. Seeker

   MRC Centre for Regenerative Medicine · University of Edinburgh

   Affiliation as printed

   University of Edinburgh, Centre for Regenerative Medicine, Edinburgh, UK

3. Nina-Lydia Kazakou

   MRC Centre for Regenerative Medicine · University of Edinburgh

   Affiliation as printed

   University of Edinburgh, Centre for Regenerative Medicine, Edinburgh, UK

4. Nadine Bestard-Cuche

   MRC Centre for Regenerative Medicine · University of Edinburgh

   Affiliation as printed

   University of Edinburgh, Centre for Regenerative Medicine, Edinburgh, UK

5. Sarah Jäkel

   Institut für Schlaganfall- und Demenzforschung · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Ludwig-Maximilians-Universitätt, Institute for Stroke and Dementia Research, Munich, Germany

6. Neil Cowan Henderson

   Centre for Inflammation Research · University of Edinburgh

   Affiliation as printed

   University of Edinburgh, Centre for Inflammation Research, Edinburgh, UK

7. Willeke van Roon‐Mom Aachen Department of Human Genetics

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   University of Leiden Medical Center, Department of Human Genetics, Leiden, the Netherlands

8. Josef Priller

   UK Dementia Research Institute · University of Edinburgh

   Affiliation as printed

   University of Edinburgh, UK Dementia Research Institute, Edinburgh, UK

9. Anna Williams

   MRC Centre for Regenerative Medicine · University of Edinburgh

   Affiliation as printed

   University of Edinburgh, Centre for Regenerative Medicine, Edinburgh, UK