B04 Environment-dependent modulation of striatal gene expression in the BACHD RAT model

Background

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in exon 1 of the huntingtin (HTT) gene that results in progressive brain neurodegeneration with highest damage in striatum. Evidence from both human and mouse model studies suggests that (i) transcriptional dysregulation may represent a major factor underlying mutant HTT (mHTT) activity and (ii) the environment can affect HD features, although the underlying mechanisms are unclear.

Aims

The aim of this study was to examine HD related early life gene-environment interactions in the BACHD rat model.

Methods/techniques

We applied maternal separation (MS) and environmental enrichment (EE) during development in BACHD rats and examined the effects on striatal gene expression, using RNA sequencing. To relate environmental effects with disease progression, we integrated our results with striatal consensus modules defined on HTT-CAG length and age-dependent co-expression gene networks.

Results/outcome

Our results show that while most gene expression changes were determined by mHTT, both environmental treatments modulated the mHTT induced alterations with distinctive and opposing effects of MS and EE on striatal consensus modules.

Conclusions

The opposite modulatory action of MS and EE in this study, may explain their antithetic effects observed on disease phenotypes in animal models of HD and other neurodegenerative disorders.