Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


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


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,

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 Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>