The research topics in the group “Functional Neurogenetics” centre around hereditary neurodegenerative diseases. Conditions studied include the spinocerebellar ataxias (SCAs), the distal hereditary motor neuropathies (dHMNs), and the hereditary spastic paraplegias (HSPs). We believe that these heterogeneous disorders represent ideal models to define the multiple requirements for long-term survival of axons and neurons. Our work is thereby conceptually embedded in the “Ageing and Age-related Diseases” focus of the Research Profile of the JenaMedicalSchool.
One major aspect of our work has been on elucidating the genetic basis of the heterogeneous disorders HMN, SCA, and HSP. Consequently, our group has contributed significantly to the definition of the mutational spectra for several disease genes. A special focus has been on the identification of copy number aberrations, i.e. a class of mutations which is hard to detect by standard genetic approaches. Some of the pertinent screens have entailed additional projects such as in-depths characterisation of the underlying mutational mechanisms, methodological improvements, and implementation of the developed screening concepts for other hereditary diseases. In addition to the studying of known genes we are actively pursuing several “gene-hunting” efforts, i.e. the identification of novel genes mutated in the above clinical conditions. Most of our clinical-genetic studies are performed in the frame of local, national, and international collaborations with renowned neurologists.
The second, more functional aspect of our work concentrates on the pathophysiology of the HSPs. This group of movement disorders is characterised by dying-back degeneration of cortico-spinal tract axons, i.e. the longest neuronal processes in the human body. The consequence is progressive leg spasticity and weakness. With >40 loci described to date, the HSPs are amongst the most genetically heterogeneous diseases. This diversity appears to also apply to the functional level: protein products of the currently ~20 known HSP genes have diverse subcellular localisations and seemingly unrelated primary roles. Recent findings, however, suggest that there may be links between forms of HSP at the level of cellular processes. Our pertinent efforts include studies on the expression, subcellular localisation, and interaction partners of selected HSP proteins. In addition, we apply appropriate in vivo disease models. We have created several murin knockout/knockin lines which are currently being characterised at the levels of phenotype, histology, primary cell culture, and intracellular ultrastructure.