The most common genetic cause of Parkinson’s disease destroys brain cells and devastates many patients worldwide, scientists have discovered. The investigators found that mutations in a gene called leucine-rich repeat kinase 2 may increase the rate at which LRRK2 tags ribosomal proteins, which are key components of protein-making machinery inside cells. This could cause the machinery to manufacture too many proteins, leading to cell death.
LRRK2 is a kinase enzyme, a type of protein found in cells that tags molecules with chemicals called phosphate groups. The process of phosphorylation helps regulate basic nerve cell function and health. Previous studies suggest that disease-causing mutations, like the G2019S mutation, increase the rate at which LRRK2 tags molecules. Identifying the molecules that LRRK2 tags provides clues as to how nerve cells may die during Parkinson’s disease.
In this study, the researchers used LRRK2 as bait to fish out the proteins that it normally tags. Multiple experiments performed on human kidney cells suggested that LRRK2 tags ribosomal proteins. These proteins combine with other molecules, called ribonucleic acids, to form ribosomes, which are the cell’s protein-making factories.
Further experiments suggested that disease-causing mutations in LRRK2 increase the rate at which it tags two ribosomal proteins, called s11 and s15. Moreover, brain tissue samples from patients with LRRK2 mutations had greater levels of phosphorylated s15 than seen in controls.
Next, the researchers investigated whether phosphorylation could be linked to cell death, by studying nerve cells derived from rats or from human embryonic stem cells. Genetically engineering the cells to have a LRRK2 mutant gene increased the amount of cell death and phosphorylated s15. In contrast, the researchers prevented cell death when they engineered the cells to also make a mutant s15 protein that could not be tagged by LRRK2.
Ian Martin, Jungwoo Wren Kim, Byoung Dae Lee, Ho Chul Kang, Jin-Chong Xu, Hao Jia, Jeannette Stankowski, Min-Sik Kim, Jun Zhong, Manoj Kumar, Shaida A. Andrabi, Yulan Xiong, Dennis W. Dickson, Zbigniew K. Wszolek, Akhilesh Pandey, Ted M. Dawson, Valina L. Dawson. Protein s15 Phosphorylation Mediates LRRK2 Neurodegeneration in Parkinson’s Disease. Cell, 2014; 157 (2): 472 DOI: 10.1016/j.cell.2014.01.064