A040 The role of metabolic hypothalamic circuitries in Huntington’s disease

<h3>Background</h3> Recent studies suggest that Huntington´s Disease (HD) and the spectrum of frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS) disorders share similar pathogenic mechanisms, including metabolic dysfunction. Interestingly, overlapping hypothalamic pathology indicative of metabolic dysregulation has been shown in clinical post-mortem tissue with HD and FTD/ALS. Additionally, the disease-associated proteins, mutant huntingtin (mHTT) and TAR-DNA-binding protein-43 (TDP-43), can exert direct pathological effects in the hypothalamus. The arcuate nucleus (Arc) of the hypothalamus is a master regulator of metabolic homeostasis. Therefore, we hypothesize that expression of mHTT or TDP-43 in the Arc can lead to pathology and metabolic dysregulation. <h3>Aim</h3> To elucidate effects of mHTT and TDP-43 in the Arc on metabolism and neuropathology in novel animal models of HD and FTD/ALS. <h3>Method</h3> Flex-switch adeno-associated viral (AAV) vectors expressing mHTT, TDP-43 or green fluorescent protein (GFP) were bilaterally injected into the hypothalamus selectively targeting neuronal expression in the Arc of mice using the cre recombinase (cre)-loxP system. Metabolic parameters and post-mortem brain tissue analyses were used to investigate specific pathological effects of over-expression of these proteins in the Arc. <h3>Results</h3> We confirmed specific expression of the transgenes in the Arc. Presence of mHTT inclusions was observed in the Arc already at 10 weeks post injection using immunohistochemistry. No change in body weight in mice overexpressing mHTT, TDP-43 or GFP was found at this time-point. <h3>Conclusion</h3> These results indicate that cells in the Arc can form mHTT inclusions. Ongoing analyses will reveal effects on metabolism and neuropathology at later time-points.