Nichols Lab Research
The Nichols Lab focuses on understanding and exploiting the Parkinson’s disease-associated protein LRRK2 as an avenue towards a preventative or therapeutic drug.
Everyone has a series of genes (the human genome) that tell every cell in the body how to function. Each gene is a segment of DNA that holds the code for a specific protein. Proteins perform the majority of functions within each cell. Genes can become mutated, meaning the DNA sequence has changed, and this may cause drastic changes in the resulting protein. In 2004, mutations in the gene LRRK2 (leucine-rich repeat kinase 2) were found to be associated with Parkinson’s disease. The LRRK2 protein, encoded by the LRRK2 gene, is a certain kind of protein called a kinase. Kinases are essential components of cells that transmit signals and control many cellular processes.
Mutations in the LRRK2 gene are the most common cause of familial (inherited) Parkinson’s disease. Importantly, most PD patients with LRRK2 mutations exhibit symptoms indistinguishable from typical, late-onset idiopathic/sporadic (no specific known cause) Parkinson’s disease. This suggests that LRRK2 is a significant player in Parkinson’s disease for those with and without mutations in the LRRK2 gene. It is a promising target for developing therapeutics and a useful tool for investigating the biochemical pathways that lead to Parkinson’s disease.
As a lab, we strive to understand LRRK2’s function in cells, both in its normal and mutated state. Through worldwide collaborations with pharmaceutical companies, biotechnology companies, and academic labs, we strive to rapidly bring target based therapies to the medical clinic and to discover the mechanisms of neurodegeneration that characterizes Parkinson’s disease.
The following are current LRRK2 studies within the Nichols lab:
- Elucidation of an LRRK2 signaling pathway. We are pursuing a variety of techniques to define upstream inputs and downstream outputs of LRRK2 kinase activity. One of our approaches is to pursue the enzymes that act on the cluster of cellular phosphorylation sites preceding the LRR domain. We are pursuing the kinases and phosphatases that act on these sites.
- Development of LRRK2 activity based assays. We are applying state of the art technologies to detect LRRK2 and its kinase activity. In collaboration with Life Technologies and funded by the Michael J Fox Foundation for Parkinson’s Research (MJFF), we are developing sensitive assays of LRRK2 activities.
- Understanding LRRK2 in patient sourced tissues and cells. The Parkinson's Institute provides a wealth of patient derived biological samples to interrogate the causes of PD. These generously donated samples include patient blood samples as well as samples from the Parkinson's Institute Brain Bank. Through internal collaborations with the Parkinson’s Institute Movement Disorders Clinic, Clinical Research, and Laboratory Research departments, we are accessing these samples to help provide insight into LRRK2. We are also evaluating the role of LRRK2 in multiple cellular processes using PD patient derived induced pluripotent stem cells (iPSCs).
Nichols Lab Funding:
The Nichols Lab is funded by grants from the Michael J. Fox Foundation for Parkinson's Research, the Department of Defense, The California Institute for Regenerative Medicine and the benevolence of the Brin/Wojicki Foundation.
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