Parkinsons disease: genetic defect triggers multiple damages in neurons

07.07.2014 - (idw) Deutsches Zentrum fr Neurodegenerative Erkrankungen e.V. (DZNE)

People whose genome carries certain variations have a particularly high risk of developing Parkinson's disease. In particular, genetic variants in a gene referred to as GBA1 (glucocerebrosidase) are associated to an increased risk for Parkinsons. Researchers of the German Center for Neurodegenerative Diseases (DZNE) and the Hertie Institute for Clinical Brain Research have now pinpointed the consequences that genetic variations in GBA1 have on neurons consequences that had been largely undetermined to date. Using stem cells, they found that mutations affecting GBA1 impair calcium metabolism and the cells garbage disposal that normally digests and recycles defective substances including alpha-synuclein, the protein that accumulates in the brain of patients suffering from Parkinsons. This research shows a link between alterations in the GBA1 gene and cellular dysfunctions in Parkinsons disease for the first time. It also suggests potential targets for drugs and biomarkers that could be useful for diagnosis. The study is published in the journal Nature Communications.

In people suffering from Parkinsons, brain cells that are supposed to produce a neurotransmitter called dopamine, die off over time, making it difficult for these patients to control their movements. They may also suffer from insomnia and depression. And as the illness progresses, they may also develop dementia. To date, there is no cure for Parkinsons disease and the actual triggers of the death of neurons, i.e. of the so-called neurodegeneration, are still unknown. However, mutations of a certain gene referred to as GBA1, have been identified as a major risk factor. This gene contains the blueprint of an enzyme, called glucocerebrosidase, that is involved in the processing of certain lipids, explains DZNE researcher Michela Deleidi, who also works at the Hertie Institute for Clinical Brain Research. Alterations in this gene do not necessarily lead to Parkinsons. In fact, whereas people with mutations in both copies of the gene are affected by a metabolic disorder called Gauchers disease, both Gauchers disease patients and individuals with a mutation in just one copy of the gene are predisposed to develop Parkinsons.

Up to now, the consequences these mutations have on nerve cells were largely unexplored. Studies addressing the effect of these mutations in Parkinsons disease have not been performed yet, observes Deleidi. She therefore set out to elucidate the consequences of the genetic mutations. The study involved a team based in Tbingen including Professor Thomas Gasser, as well researchers in Italy and the United States.

Induced stem cells

Human nerve cells are not readily accessible and it is very difficult to cultivate such cells in the laboratory if they are obtained, for instance, through a surgical procedure. Hence, Deleidi and her colleagues chose a different approach: they took skin cells from Parkinsons and Gauchers patients harbouring mutations of the GBA1 gene and converted them into induced pluripotent stem cells by manipulating their genetic programme. Stem cells are unspecialized cells that have the potential to evolve into virtually any type of cell in the body. We differentiated stem cells into dopamine-producing neurons, the scientist explains. These cells contained the patients DNA and therefore also the GBA1 gene mutations. Next, we investigated the effects that these mutations had on the cell. We looked at those effects which make the cell susceptible to neurodegeneration. Other neurons that also originated from patients, served as controls. However, in these cells the GBA1 mutations had been corrected by genetic engineering.

Various dysfunctions

Potential biomarkers

These results were consistent with other findings based on patient studies. Enzymes showing unusual behavior in the cell cultures also revealed reduced activity in the spinal fluid of patients. This comprised not only glucocerebrosidase. The activity of other enzymes involved in the metabolism of lipids was also reduced. Measurement of the enzyme activity may provide important clues to disease. These enzymes may serve as biomarkers, in other words as indicators that could be helpful for the diagnosis of Parkinson's disease, Deleidi points out.

The researchers also found increased concentrations of the protein alpha-synuclein in the nerve cells they studied in laboratory. This protein does play a key role in Parkinsons disease because it aggregates into microscopically small lumps, which are suspected to damage nerve cells.

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Parkinsons disease: genetic defect triggers multiple damages in neurons