Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Parkinson‘s disease: genetic defect triggers multiple damages in neurons

07.07.2014

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.

Various dysfunctions

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.

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 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.”

Original Publication

“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

Further reports about: DNA DZNE Parkinson’s activity biomarkers defect effects enzyme enzymes explains involved metabolism mutations neurons triggers

More articles from Life Sciences:

nachricht Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>