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
Water forms 'spine of hydration' around DNA, group finds
26.05.2017 | Cornell University
How herpesviruses win the footrace against the immune system
26.05.2017 | Helmholtz-Zentrum für Infektionsforschung
Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.
Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
26.05.2017 | Life Sciences
26.05.2017 | Life Sciences
26.05.2017 | Physics and Astronomy