The causes of multiple system atrophy (MSA), a particularly severe form of Parkinson’s disease, have for a long time remained unknown. Researchers at the Hertie Institute for Clinical Brain Research in Tübingen have now shown that hereditary gene variants considerably increase the risk of contracting MSA.
A study that was part of the National Genome Research Network (NGFN) and carried out in cooperation with several European and American research groups, has changed the understanding of MSA, which was previously regarded as a sporadically occurring disease. Around five to ten out of 100,000 people suffer from MSA, which is the most frequent type of what are referred to as “atypical” Parkinson’s syndromes. The majority of MSA sufferers contract the disease between the ages of 50 and 60 and death follows on average nine years after initial diagnosis of the disease.
The study entitled "SNCA variants are associated with increased risk of multiple system atrophy" which was published in the April edition of "Annals of Neurology", showed for the first time that variations of the alpha-synuclein (SNCA) gene are associated with an elevated risk of contracting MSA.
"The complex MSA syndrome and Parkinson's disease (PD) have a number of similarities, which is why we have also investigated in MSA patients single nucleotide polymorphisms (SNPs, nucleotide exchanges) that occur in Parkinson's patients," said Professor Dr. Thomas Gasser (director of the Hertie Institute for Clinical Brain Research) describing how the researchers first became interested in MSA.
In a previous, genome-wide association study, the researchers examined 1713 PD patients and identified 384 SNPs with a nominally significant association with PD (Scholz, S. and Schulte, C., Annual Meeting of The American Society of Human Genetics, Nov 2008). The researchers then screened 413 MSA patients for the presence of these 384 SNPs. They selected the ten most significant SNPs identified in the association study and screened an independent cohort of 108 MSA patients for these SNPs in a second study. "We found that two of the SNPs had a significant association with MSA and that the carriers of these SNPs had a six-fold higher risk of contracting MSA. These two SNPs are located in the SNCA locus," said Claudia Schulte, who is one of the lead authors of the study.
It is still unknown why similar genetic modifications of the alpha synuclein gene lead to typical Parkinson’s in some patients and to the severe form of MSA in others. “We assume that the gene variants that have been discovered have an effect on the regulation of the production and distribution of the alpha synuclein protein in the cell,” explained Dr. Manu Sharma, another major contributor to the study. This finding might give the scientists some idea of which mechanism leads to the development of the disease. If the researchers succeed in obtaining a greater understanding of the defective regulation processes, this might even open up new strategies for the medical treatment or prevention of the processes that cause the disease. Two of the four lead authors, Claudia Schulte and Dr. Manu Sharma, are researchers at the Hertie Institute for Clinical Brain Research, a project jointly shared between the Hertie Foundation and the University of Tübingen. The study was financed with a grant from the German Federal Ministry of Education and Research (BMBF) as part of the National Genome Research Network (NGFN).
Literature: SNCA variants are associated with increased risk of multiple system atrophySonja W. Scholz, Henry Houlden, Claudia Schulte, Manu Sharma (lead authors)Abi Li, Daniela Berg, Anna Melchers, Reema Paudel, J. Raphael Gibbs, Javier Simon-Sanchez, Coro Paisan-Ruiz, Jose Bras, Jinhui Ding, Honglei Chen, Bryan J. Traynor, Sampath Arepalli, Ryan R. Zonozi, Tamas Revesz, Janice Holton, Nick Wood, Andrew Lees, Wolfgang Oertel, Ullrich Wüllner, Stefano Goldwurm, Maria Teresa Pellecchia, Thomas Illig, Olaf Riess, Hubert H. Fernandez, Ramon L. Rodriguez, Michael S. Okun, Werner Poewe, Gregor K. Wenning, John A. Hardy, Andrew B. Singleton, Thomas Gasser
Annals of Neurology, Volume 9999, Issue 999A, Pages NA,Published Online: Mar 18 2009DOI: 10.1002/ana.21685
Further information:Tübingen University HospitalCentre of NeurologyHertie Institute for Clinical Brain ResearchProfessor Dr. Thomas GasserTel.: +49 (0)7071/29-8 20 48E-mail: thomas.gasser(at)med.uni-tuebingen.de