Gasser Lab

Genetics of Parkinson's Disease

Genetic causes of the sporadic Parkinson's disease

The genetic variants known today can only explain a small part of the overall risk of disease. In order to obtain a more complete picture of the entire genetic risk profile and to derive new approaches for diagnosis, prevention or therapy, as complete genetic data sets as possible must be examined by many thousands of patients. In large international consortia, such as the International Parkinson's Disease Genomics Consortium (IPDGC), the research group conducts such studies in collaboration with many colleagues from around the world (Simon-Sanchez et al., Nat Genet, 2009, Nalls et al., Nat Genet 2014).

Contact: Prof. Dr. T. Gasser, Prof. D. Berg

Leucine rich repeat kinase 2, LRRK2 (Park8)

In 2004, the group was able to identify mutations in the LRRK2 gene (Leucine rich repeats kinase 2) in two large families with inherited Parkinson's disease (Zimprich et al., Neuron 2004). This discovery was taken up by many other groups around the world, and it turned out that LRRK2 mutations are the most common cause for autosomal dominant Parkinson's syndrome. Although all patients from affected families have mutations in the same gene, there is a remarkable heterogeneity both in terms of clinical appearance and neuropathological findings. For example, the spectrum of found protein aggregates of typical Lewy corpuscles or tau-positive neurofibrils suffices to the complete absence of both aggregate forms. The elucidation of the molecular pathomechanism of the disease caused by LRRK2 mutations could therefore be important for synucleinopathies (Lewy corpuscles) as well as for tauopathies (neurofibrils). This suggests a central role of the gene product in the pathogenesis of various neurodegenerative diseases with Parkinson's disease.

Contact: Prof. Dr. T. Gasser

Courage-PD: Comprehensive Unbiased Risk factor Assessement for Genetics and Environment in Parkinson‘s Disease

This multi-national project, funded under the "Joint Programming for Neurodegenerative Disease (JPND)", will combine genetic, epidemiological and cell biology approaches to contribute to a better understanding of the development of Parkinson's disease. Particular attention is paid to the interaction of genetic and environmental factors in the development of the disease. Risk factors are then examined in cell culture models based on the iPS (induced pluripotent stem cells) technology for their functional effects.

Contact: Prof. Dr. T. Gasser, Prof. Dr. R. Krüger, Dr. M. Sharma

Dystonia

The identification of ATP1A3 for rapid onset dystonia parkinsonism and MR-1 for paroxysmal non-kinesiogenic dyskinesia revealed interesting new insights into pathways of the brain that may be involved in dystonia development. The hitherto set thematic focus on the characterization of the genetic and molecular pathogenetic aspects of torsin A and epsilon sarkoglycan have been continued and intensified.

Myoclonus-dystonia

Genetics and molecular pathogenesis of myoclonus dystonia

Myoclonus dystonia (M-D, DYT11) is a dystonia-plus syndrome, in which the patients suffer from focal or segmental dystonia in addition to "lightning" myoclonia.

Our previous mutation screening demonstrated heterozygous exonian mutations in the gene for epsilon sarkoglycan (SGCE) in over 80% of familial cases. Genetic heterogeneity has also been assumed for the other families, which is supported by the mapping of an alternative gene locus on chromosome 18 (DYT15)(Grimes et al 2002).

However, the etiology of the sporadic, almost in all cases, mutation-negative cases of SGCE is still insufficiently understood. We analyzed the promoter sequence of 40 sporadic patients who clinically met the criteria of myoclonus dystonia. It was found that the promoter region is highly conserved. Only a few SNP variations could be found. In the next step, the effect of these polymorphisms on the SGCE expression level will be investigated by luciferase assays.

No role is played by SGCE in the pathogenesis of sporadic Gilles de la Tourette cases in a cohort of 83 German index patients. Exonian mutations could be excluded. There was no evidence for a genetic association of GTS with the 7q21 region. The molecular biology work on the generation of a conditional mouse model for SGCE was continued and further protein-chemical phenotyping experiments were established. The cooperation with the Neurological Clinic of LMU, Munich (Prof. Dr. T. Brandt, Dr. A. Deutschländer) was continued with Voxel-based morphometry (VBM) investigations. Interestingly, with this volumetric method, similar regions of interest are found as with the functional nuclear spin measurements. These are frontal cortical and subcortical structures involving the thalamus.