About 10 percent of Parkinson's disease occur in people under the age of 50 (juvenile Parkinson's disease). However, in most cases, the disease cannot be traced back to the known genetic mutations. For this reason, the Californian researchers have taken cells from Parkinson's patients suffering from the juvenile form of the disease and from non-patients for comparison and converted them into induced pluripotent stem cells (iPSC) in order to produce dopamine neurons from each patient. Then, they cultivated the cells in a dish and analyzed the functions of the differentiated dopaminergic cells of the midbrain.

The scientists around Dr. Clive Svendsen from the Cedars-Sinai Board of Governors Regenerative Medicine Institute initially observed that the cells of Parkinson's patients showed an increased accumulation of soluble α synuclein proteins and phosphorylated protein kinase Cα, but also a reduced frequency of lysosomal membrane proteins such as LAMP1 (lysosomal-associated membrane protein 1). LAMP1 is a transmembrane protein expressed in high or medium concentrations in many normal tissue cell types. It is located primarily in lysosomal membranes and supplies adhesion proteins with carbohydrate ligands.

The scientists followed up this indication and tested the function of the lysosomes with a specific phorbol ester. Phorbol is a substance from spurge plants, the ester is toxic and activates protein kinase C, which plays an important role in signal transduction. As a result, the amount of α synuclein was reduced by degradation with the help of protein complexes and phosphorylated protein kinase Cα and at the same time, the LAMP1 frequency increased.

They concluded that there could be other genetic contributions to juvenile Parkinson's disease. Svendson suspects that the dopamine neurons of these Parkinson's patients may misprocess α synuclein over a period of 20 or 30 years and thereby cause the Parkinson's symptoms.

The induced pluripotent stem cells, which were altered by mutation, showed a signature, which could be normalized by specific phorbol esters, which makes them promising therapeutic candidates according to the scientists.

Original publication:
A. H. Laperle, S. Sances, N. Yucer, V. J. Dardov, V. J. Garcia, R. Ho, A. N. Fulton, M. R. Jones, K. M. Roxas, P. Avalos, D. West, M. G. Banuelos, Z. Shu, R. Murali, N. T. Maidment, J. E. Van Eyk,
M. Tagliati & C. N. Svendsen (2020). iPSC modeling of young-onset Parkinson's disease reveals a molecular signature of disease and novel therapeutic candidates. Nature Medicine 26: 289-299.
https://doi.org/10.1038/s41591-019-0739-1.

Further information:
https://www.sciencedaily.com/releases/2020/01/200127134825.htm
https://www.cedars-sinai.org/research/labs/svendsen/members.html