The mutation G2019S in the gene LKKR2 was first described in 2004. People with this mutation in the LKKR2 gene, which codes for an important enzyme (serine/threonine kinase), have an up to 17-fold increased risk of developing Parkinson's disease (1, 2).

An international team of researchers led by Prof. Jens Schwarmborn from the Luxembourg Centre for Systems Biomedicine (LCSB) at the University of Luxembourg converted induced pluripotent stem cells from patients suffering from Parkinson's disease bearing these G2019S mutationand from healthy donors into neuroepithelial stem cells to investigate early influences on the neurodevelopment. Neuroepithelial stem cells are early neural stem cells (3). They simulate early brain development.

In addition, a line from the mutated cells of Parkinson's patients has been corrected by means of genetic engineering and, conversely, a mutation in the LKK2 gene of the healthy donors was generated by genetic engineering als controls. The neuroepithelial stem cell cultures with the mutation G2019S were able to recapitulate important mitochondrial defects that had previously only been investigated  using differentiated dopaminergic neurons.

By combining high-content imaging approaches, 3D image analysis, and functional mitochondrial measurements, the scientists found that cells with the LRRK2-G2019S mutation exhibited a significantly altered morphology and functionality of the mitochondria compared to controls. The neuroepithelial stem cells with LRRK2-G2019S mutation showed an increased number of mitochondria compared to the controls. However, they were severely fragmented and showed fissures as well as a reduced membrane potential. The ability of the cells to perform mitophagy was also disturbed. This means that damaged mitochondria are specifically degraded with the help of lysosomes. The cells were also more vulnerable to the release of reactive oxygen species than the reference cells.

These results with neuronal precursor stem cells confirmed the hypothesis that early mitochondrial developmental disorders can contribute to the manifestation of the Parkinson's  pathology in later life. With their investigations, the scientists emphatically point out a connection between early deregulated neurogenesis and the onset and progression of a later Parkinson's disease, which means that Parkinson's disease is not only a neurodegenerative disease, but also a  developmental disorder.

The scientists have published their results in the Journal Stem Cell Reports:
Walter, J., Bolognin, S., Antonius, P. M. A., Nickels, S. L., Poovathingal, S. K., Salamanca, L., Magni, S., Perfeito, R., Hoel, F., Qing, X., Jarazo, J., Arias-Fuenzalida, J., Ignac, T., Monzel, A. S., Gonzalez-Cano, L., Pereira de Almeida, L., Skupin, A., Tronstad, K. J. & Schwamborn, J. C. (2019). Neural Stem Cells of Parkinson’s Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality. Stem Cell Reports 12: 1-12. https://doi.org/10.1016/j.stemcr.2019.03.004

Source and more information:
https://wwwfr.uni.lu/lcsb/research/developmental_and_cellular_biology/research_projects

Additional information:
(1) Bonifati, V. (2006). Parkinson's Disease: The LRRK2-G2019S mutation: opening a novel era in Parkinson's disease genetics. European Journal of Human Genetics 14: 1061–1062. https://www.nature.com/articles/5201695
(2) M. Steger, F. Tonelli, G. Ito, P. Davies, M. Trost, M. Vetter, S. Wachter, E. Lorentzen, G. Duddy, S. Wilson, M. A. S. Baptista, B. K. Fiske, M. J. Fell, J. A. Morrow, A. D. Reith, D. R. Alessi & M. Mann (2016). Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. eLife. DOI: http://dx.doi.org/10.7554/eLife.12813
(3) https://cordis.europa.eu/project/rcn/101630/brief/de