Research Marion Decrop

Abstract

Huntington's disease (HD) is an incurable hereditary neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene, leading to the accumulation of mHTT aggregates. While the precise mechanisms related to the impairment of the direct and indirect dopaminergic pathways of the basal ganglia remain unclear, recent evidence indicated somatic instability (SI) as a key driver of HD pathogenesis. In particular, the DNA mismatch repair gene MSH3 has been identified as one of the major players to promote SI, as recent work indicated that modulation of Msh3 leads to significantly reduced mHTT aggregate formation. However, it remains elusive whether modulation of Msh3, and thus SI, could improve the brain's functional activity, especially within the severely affected dopaminergic pathways. In this project, I will examine the functional integrity of the direct and indirect dopaminergic pathways and assess the longitudinal effect of global Msh3 knockout for the treatment of HD. By combining advanced pharmacological MRI with electrophysiology, proteomics, and molecular analyses in a multidisciplinary approach, this will be the first project to provide an understanding of the impact of targeting somatic instability on the functional integrity of the dopaminergic pathways. The outcomes of this research will provide key insights for the development of novel therapies aimed at SI, not only for HD but also for other disorders involving CAG repeats.

Researcher(s)

• Promoter: Bertoglio Daniele
• Co-promoter: Ellender Tommas
• Co-promoter: Verhoye Marleen
• Fellow: Decrop Marion

Research team(s)

• Bio-Imaging lab

Project type(s)

• Research Project

Abstract

Huntington's disease (HD) is a rare, autosomal dominant inherited neurodegenerative disorder caused by an expanded polyglutamine sequence in the huntingtin gene (HTT) encoding for mutant huntingtin (mHTT). HD neuropathology is characterized by basal ganglia neurodegeneration, leading to progressive motor, psychiatric, and cognitive impairments, and ultimately death. While the pathogenic mechanisms by which mHTT causes selective dysfunction of the medium-size spiny neurons (MSNs) in the basal ganglia remain uncertain, we have extensive (pre)clinical evidence on the progressive loss of both D1 receptors (D1R) and D2 receptors (D2R), involved in direct and indirect dopaminergic pathways, respectively. Although MSN degeneration occurs roughly in equal proportions for D1R and D2R, the indirect dopaminergic pathway is affected first, resulting in the occurrence of the involuntary movements (hyperkinesia) characteristic of HD. As of today, there is a substantial knowledge gap in understanding the relationship between dopaminergic receptor density and the functional signalling of both direct and indirect dopaminergic pathways. In this project, a multimodal approach will be applied consisting of advanced non-invasive functional magnetic resonance imaging (fMRI), electrophysiology, behaviour, and post-mortem techniques in HD mouse models, with specific modulation of the direct or indirect dopamine pathway. The outcome will increase our understanding of the functional integrity of both dopaminergic pathways of the basal ganglia in HD.

Researcher(s)

• Promoter: Bertoglio Daniele
• Fellow: Decrop Marion

Research team(s)

• Bio-Imaging lab

Project type(s)

• Research Project