American scientists led by Prof. Han Seok Ko from Johns Hopkins University in Baltimore, Maryland, have found a genetic mutation that may be responsible for the development of Parkinson's disease and plaque development in the brain.

The GBA1 gene encodes an enzyme that metabolises fat molecules in the cell. fat molecules in the cell Membrane have the function of holding proteins together in a certain way. If the gene mutates, the composition of the fat molecules in the cell wall changes resulting in an increased formation of fat in the cells. The Researchers suppose that the quantities of fat let protein fragments (alpha-synucleins) stick together in the brain forming the so-called "Lewy bodies". This impairs learning, behaviour and mobility.

 

There are also alpha-synucleins in healthy cells. However, individual proteins combine to form groups (tetramers), which makes them more resistant to aggregation in the brain. But in the case of the Parkinson's disease, individual alpha-synucleins stick together on the cell membranes thus make it impossible for the neurons to communicate proberly with each other. The alpha-synuclein tetramers can no longer be held in place which have a damaging effect in the cell.

 

For their investigations, the scientists used human neuron cells, which they had genetically modified with the CRISPR-Cas9-technology. In this way, they mutated GBA1 artificially and observed that a fat molecule called glucoseramide increased. At the same time, the number of synuclein tetramers decreased. They treated the cells with miglustat and were able to stop this process. Miglustat is a drug used in the treatment of two rare hereditary metabolic diseases.

The scientists assume that increased amounts of glucoseramide destabilize fat molecules in the membrane, thereby disintegrating the alpha-synuclein tetramers.

The scientists have published their work in the Journal Proceedings of the National Academy of Sciences.

Sangjune Kim, Seung Pil Yun, Saebom Lee, George Essien Umanah, Veera Venkata Ratnam Bandaru, Xiling Yin, Peter Rhee, Senthilkumar S. Karuppagounder, Seung-Hwan Kwon, Hojae Lee, Xiaobo Mao, Donghoon Kim, Akhilesh Pandey, Gabsang Lee, Valina L. Dawson, Ted M. Dawson and Han Seok Ko (2018). GBA1 deficiency negatively affects physiological a-synuclein tetramers and related multimers. PNAS 115 (4) 798-803. http://www.pnas.org/content/115/4/798

 

Source:
https://www.hopkinsmedicine.org/news/media/releases/faulty_cellular_membrane_mix_linked_to_parkinsons_disease