Cellular and molecular mechanisms in the limbic system for the psychiatric manifestation of Huntington disease

The aim of the project is to identify key cellular and molecular mechanisms for psychiatric symptoms in Huntington disease (HD). HD is a fatal neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. There is no disease-modifying treatment. Previous research has mainly focused on the typical movement disorder in HD.

As psychiatric manifestations often are the earliest part of the disease, identification of the underlying biology may unravel novel targets for therapeutic interventions.

Recent data indicate shared pathogenic mechanisms with neurodegenerative disorders characterized by pathology with transactive response DNA binding protein of 43 kDa (TDP43).

Our preliminary work show effects on SIDT2, a regulator of RNA degradation, in limbic regions in HD and TDP43 related disorders.

This project will test the hypothesis that expression of mutant HTT and TDP43 disrupts RNA metabolism in specific limbic circuitries via interaction with SIDT2, leading to the development of psychiatric symptoms.

Effects of targeted genetic modulation of HTT or TDP43 as well as SIDT2 will be tested in relevant animal models and with a battery of tests for psychiatric manifestations of the disorders. Unique sets of clinical material of postmortem human brain tissue will be investigated.

The proposed project will advance the understanding of underlying mechanisms of psychiatric symptoms and may identify novel targets for therapeutic intervention for HD and related disorders.