The team of the Huntington Disease research group.

Huntington's Disease

Huntington Disease (HD) is an autosomal dominantly inherited, progressive neurodegenerative disorder, which is characterized by psychiatric disturbances, cognitive decline and motor deficits. Most HD patients develop symptoms between 35 and 45 years of age. Until now no effective treatment exists to halt the progression of the disease, which leads to an early death usually 10-15 years after the onset of first symptoms.  HD is caused by a CAG repeat expansion in exon 1 of the HTT gene and therefore it belongs to the group of several polyglutamine diseases.

Our group focuses on the generation and characterization of transgenic rat models for HD. Compared to mice rats are generally less aggressive and exhibit excellent cognitive abilities, which are required to identify subtle deficits in early stages of HD. Other practical advantages of rats are their larger body size, which facilitates invasive in vivo procedures such as sampling of blood and CSF, repeated physiological measurements and surgical interventions. To this end we have developed two unique transgenic rat models for HD, which demonstrate a progressive neurological phenotype and HD specific neuropathological changes. These rat models are highly suited for longitudinal monitoring with behavioral tests and neuroimaging as well as for long-term treatment with novel compounds and many other therapeutic approaches such as microsurgery and stem cell transplantation. Therefore, in collaboration with partners from the pharmaceutical industry and the CHDI Foundation we intend to use these rat models for preclinical trials to test the efficacy of potential therapeutics.

Another focus of our group is the identification of SNPs and other variants that modify the age of onset in HD. Apart from the CAG repeat length of the HTT gene other genetic modifiers have been shown to influence the age of onset in HD. For example we have identified genetic modifiers in the genes HAP1, ATG7 and PGC-1a in our collective of DNA samples from more than 1000 HD Patients. Further functional analyses are currently ongoing and might point to novel targets for therapeutic intervention.

Moreover, we are interested in elucidating the molecular pathomechanisms that underlie HD, e.g. mitochondrial dysfunction or huntingtin cleavage by calpains or caspases. We are also investigating pathways that might be shared with other neurodegenerative diseases such as Spinocerebellar Ataxias or Parkinson Disease. For an overview of ongoing projects please refer to the panel on the left.