The gene GBA1 codes for the enzyme glucocerebrosidase. This enzyme is involved in the processing of certain cellular fats. It degrades glucocerebroside, a lipid that contains carbohydrates, which normally occurs during the degradation of blood cells. It is located in the lysosomes, an organelle type in large phagocytes (macrophages). Due to errors in the genetic blueprint for the enzyme, glucocerebrosidase is produced either in a reduced amount or in inferior quality. If the enzyme does not work, proteins are stored in the cells, for instance alpha-synuclein, which is found as deposits in the brains of patients suffering from Parkinson’s disease. People may also suffer from the so-called Gaucher disease, during which it can come to deposits in macrophages leading to a release of cytokines followed by inflammatory destruction of internal organs and other serious ailments.

Since 2004 it has been known that gene mutations at GBA1 leading to an erroneous glucocerebrosidase enzyme are found in patients suffering from Parkinson’s disease and that this disease may occur in such patients under certain conditions earlier in life than in patients without this mutation. However, it was not previously known what kind of consequences the mutation has for the nerve cells.

In order to study the genes, the researchers cultivated induced pluripotent stem cells (iPS) generated from skin biopsies of mutation-bearing Parkinson’s and Gaucher patients. The stem cells obtained had the same genetic defect as the patients’ output cells from the skin. The researchers used the cultivated iPS cells to culture dopaminergic neurons. For comparison they examined nerve cells in which the genetic defect had been corrected via genetic engineering methods. They compared the enzyme activities of the different cells and found that in the cells with the GBA1 defect the glucocerebrosidase activity was reduced. In addition, the calcium homeostasis was disturbed.

Source (in German):
http://idw-online.de/pages/de/news595133

Original publication:
David C. Schoendorf, Massimo Aureli, Fiona E. McAllister, Christopher J. Hindley, Florian Mayer, Benjamin Schmid, S. Pablo Sardi, Manuela Valsecchi, Susanna Hoffman, Luke Kristoffer Black, Ulrike Hedrich, Daniela Berg, Lamya S. Shihabuddin, Jing Hu on Jan Pruszak, Steven P. Gygi, Sandro Sonnino, Thomas Gasser, Michela Deleidi (2014): iPSC-derived neurons from Parkinson's disease-associated GBA1 patients show autophagic defects and impaired calcium homeostasis. Nature Communications, 2014 http://dx.doi.org/10.1038/ncomms5028