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 Parkinson’s. 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 cell’s “garbage disposal” that normally digests and recycles defective substances including alpha-synuclein, the protein that accumulates in the brain of patients suffering from Parkinson’s. This research shows a link between alterations in the GBA1 gene and cellular dysfunctions in Parkinson’s 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 Parkinson’s, 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 Parkinson’s 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 Parkinson’s. In fact, whereas people with mutations in both copies of the gene are affected by a metabolic disorder called Gaucher’s disease, both Gaucher’s disease patients and individuals with a mutation in just one copy of the gene are predisposed to develop Parkinson’s.”
Up to now, the consequences these mutations have on nerve cells were largely unexplored. “Studies addressing the effect of these mutations in Parkinson’s 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 Tübingen 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 Parkinson’s and Gaucher’s 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.
Conclusions: While the cells carrying corrected DNA did not show irregularities, the researchers found various dysfunctions in the mutated neurons. The effects were similar in cells obtained from individuals suffering from Parkinson’s and in cells from Gaucher’s patients. First, the activity of glucocerebrosidase was reduced, in addition the overall cells’ ability to process and dispose of certain metabolites was impaired. “The activity of the corresponding enzymes was lower than normal. This means that certain substances accumulate and damage the neurons,” the researcher explains.
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 Parkinson’s disease because it aggregates into microscopically small lumps, which are suspected to damage nerve cells.
Potential approaches to treatment
In addition, the calcium metabolism was impaired in neurons with mutated DNA. Whenever calcium levels rise, this has a signaling effect that triggers various cellular processes. “We found that the mutant neurons could not properly regulate the concentration of calcium ions and this makes them more vulnerable to cellular stress. They are therefore more sensitive to disturbances,” Deleidi observes. “Importantly, calcium metabolism may be a target for novel therapeutic interventions. In summary, our study clearly shows that there is a direct link between mutations in the GBA1 gene and cellular dysfunctions. Thus, you may start early in the chain of events and try to enhance the activity of the enzyme glucocerebrosidase to prevent or delay the disease.”
“iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis”, David C. Schöndorf, Massimo Aureli, Fiona E. McAllister, Christopher J. Hindley, Florian Mayer, Benjamin Schmid, S. Pablo Sardi, Manuela Valsecchi, Susanna Hoffmann, Lukas Kristoffer Schwarz, Ulrike Hedrich, Daniela Berg, Lamya S. Shihabuddin, Jing Hu, Jan Pruszak, Steven P. Gygi, Sandro Sonnino, Thomas Gasser, Michela Deleidi, Nature Communications, 2014, http://dx.doi.org/10.1038/ncomms5028
Dr. Marcus Neitzert | idw - Informationsdienst Wissenschaft
Perseus translates proteomics data
27.07.2016 | Max-Planck-Institut für Biochemie
Severity of enzyme deficiency central to favism
26.07.2016 | Universität Zürich
Transparent electronics devices are present in today’s thin film displays, solar cells, and touchscreens. The future will bring flexible versions of such devices. Their production requires printable materials that are transparent and remain highly conductive even when deformed. Researchers at INM – Leibniz Institute for New Materials have combined a new self-assembling nano ink with an imprint process to create flexible conductive grids with a resolution below one micrometer.
To print the grids, an ink of gold nanowires is applied to a substrate. A structured stamp is pressed on the substrate and forces the ink into a pattern. “The...
A new Fraunhofer MEVIS method conveys medical interrelationships quickly and intuitively with innovative visualization technology
On the monitor, a brain spins slowly and can be examined from every angle. Suddenly, some sections start glowing, first on the side and then the entire back of...
Researchers at the U.S. Department of Energy's (DOE) Ames Laboratory have discovered an unusual property of purple bronze that may point to new ways to achieve high temperature superconductivity.
While studying purple bronze, a molybdenum oxide, researchers discovered an unconventional charge density wave on its surface.
Munich Physicists have developed a novel electron microscope that can visualize electromagnetic fields oscillating at frequencies of billions of cycles per second.
Temporally varying electromagnetic fields are the driving force behind the whole of electronics. Their polarities can change at mind-bogglingly fast rates, and...
Breakup of continents with two speed: Continents initially stretch very slowly along the future splitting zone, but then move apart very quickly before the onset of rupture. The final speed can be up to 20 times faster than in the first, slow extension phase.phases
Present-day continents were shaped hundreds of millions of years ago as the supercontinent Pangaea broke apart. Derived from Pangaea’s main fragments Gondwana...
15.07.2016 | Event News
15.07.2016 | Event News
11.07.2016 | Event News
27.07.2016 | Earth Sciences
27.07.2016 | Materials Sciences
27.07.2016 | Earth Sciences