Brain or periphery in Huntington´s disease? Organ system cross-talk providing targets for novel disease modification

Huntingtons diseae (HD) is a devastating autosomal dominant neurodegenerative disorder characterised by classical neurological symptoms, such as progressive cognitive, motor and psychiatric impairments. Pathology in HD is not however limited to the brain. The causative gene and the protein huntingtin is widely expressed throughout the body.

Similar to HD patients, transgenic HD mice loose weight progressively. A higher BMI is linked to a slower progression in HD: why is unknown. Alterations in energy metabolism, has long been associated with ageing and neurodegeneration.

Our data show that white adipose tissue and skeletal muscle alterations largely contribute to metabolic alterations in HD. Today, disease modification targeting central pathology in HD is under evaluation.

Understanding peripheral pathology and the need to find strategies targetting whole body in HD is evident.The overriding aim of this project is to delineanate how mutant huntingtin (mHtt) affects whole body energy metabolism and establish whether disease modification will be obtained targeting peripheral tissue.

This approach will provide markers of disease progression and novel therapeutic targets.To meet the aim, we propose a series of key experiments to study mHtt related pathology in order to dissect mechanisms, centrally and peripherally, related to metabolism and how these contribute to HD catabolism and disease progression.