Interaction of LRRK2 and Alpha-Synuclein in PARKINSON’S Neurodegeneration
Studies have shown that in PARKINSONIAN brains, the mutated LRRK2 gene causes clumps of protein to form within neurons and an increase of kinases to develop. Ultimately, the cells die. In this particular study, researchers wanted to know if the increase of kinase was the cause of cell death or merely part of the reaction.
Early in his post doctoral work, Steve Finkbeiner, M.D., PhD, was not happy with the slow progress of examining cells and neurons one at a time. So he developed a robotic microscope that could examine multiple cells over periods of time and track their development or reaction to various other factors and agents. By using this unique robotic microscope, Dr. Gaia Skibinski and Dr. Finkbeiner of the Gladstone Institutes in San Francisco, CA, they were able to look at the long term progression within the individual cells rather than simply observing what happened to entire populations of cells.
To study this process, they developed two types of cells, one from rats genetically bred with a mutant LRRK2 gene. The second set came from induced pluripotent stem cells developed from the skin of people with the genetic LRRK2 variation of PARKINSON’S DISEASE. These human cells were a mirror image of what is actually happening in the brain cells of affected people. As they studied the development and progression of these cells, they found that it was neither the kinase activity nor the build up of LRRK2 proteins within the cells that lead to cell death, but rather the diffuse accumulation of the mutant LRRK2 gene.
Then they made an unanticipated discovery. Another protein, alpha-synuclein, long associated with PARKINSON’S DISEASE, was also building up in some of the cells. The relationship between LRRK2 and alpha synuclein has not been clearly understood. Dr. Skibinski found that removing the alpha synuclein proteins from the cells immediately reduced the levels of LRRK2 and brought a dramatic decrease in cell death. This unexpected discovery may well lead to better understanding of the relationship and roles of these proteins in neurodegeneration. Dr. Finkbeiner said “Our discovery of this ‘synergy’ between two proteins long known to play a role in PARKINSON’S is a huge step towards developing drugs that attack the disease’s underlying mechanisms. As we continue to unravel the precise functional relationship between alpha synuclein and LRRK2, we are well on our way to halting the onslaught of PARKINSON’S on the brain.”
G. Skibinski, K. Nakamura, M. R. Cookson, S. Finkbeiner.Mutant LRRK2 Toxicity in Neurons Depends on LRRK2 Levels and Synuclein But Not Kinase Activity or Inclusion Bodies. Journal of Neuroscience, 2014; 34 (2): 418 DOI: 10.1523/JNEUROSCI.2712-13.2014
Review by Marcia McCall