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Photo of Mark Cookson, Ph.D. Mark R. Cookson, Ph.D., Senior Investigator
Chief, Cell Biology and Gene Expression Section
Laboratory of Neurogenetics

Biography: Dr. Mark R. Cookson is a cell biologist whose current research interests include the effects of mutations in the genes associated with neurodegeneration at the cellular and molecular level. His laboratory efforts are directed at finding the underlying pathways that lead to Parkinson's disease and related disorders. Dr. Cookson received both his B.Sc. and Ph.D. degrees from the University of Salford, UK in 1991 and 1995, respectively. His postdoctoral studies included time spent at the Medical Research Council laboratories and at the University of Newcastle, Newcastle, UK. He joined the Mayo Clinic, Jacksonville, Florida, as an Assistant Professor in 2000 and moved to the NIA in February 2002. Within the Laboratory of Neurogenetics, Dr. Cookson's group works on the effects of mutations associated with Parkinson's disease on protein function.
Overview: Parkinson's disease is one of the major age-related neurodegenerative disorders and is characterized by the progressive loss of neurons over time. Some of the major symptoms of Parkinson's relate to the ability of the patient to initiate or stop movement and these symptoms are related to loss of neurons that express the neurotransmitter dopamine in a region of the brain called the substantia nigra. One of the major mysteries about Parkinson's disease and other neurodegenerative disorders is that for most patients the root cause remains unidentified. However, in the last decade several rare families have been found where a disease is inherited whose symptoms overlap with typical Parkinson's disease. Our work is aimed at using this genetic information to understand the pathways involved that lead to neuronal damage and death.
The major project in the laboratory follows discoveries by NIA scientists that mutations in the gene Leucine-rich repeat kinase 2 (LRRK2) cause a common form of dominantly inherited Parkinson's disease. We have shown that some mutations alter the kinase activity of LRRK2 while others change how that activity is regulated. In either case, this activity is crucial for causing neuronal degeneration, at least in cell culture models. We have therefore suggested that the kinase activity of LRRK2 is a potential therapeutic target for Parkinson's disease. Active areas of research include identifying altered signaling pathways in cells in the presence of dominant LRRK2 mutations and development of new tools to understand protein function. We are also interested in another gene that causes dominant Parkinson's disease, alpha-synuclein, which codes for an abundant synaptic protein of unclear function. Like LRRK2, alpha-synuclein is toxic to cells in culture, through mechanisms that are currently unclear but are being investigated in our laboratory. The overall aim of this project is to understand why neurons are damaged when either of these genes is mutated and to develop new ways to block these problems.
A second area of interest is in the genes that cause recessive, early onset Parkinson's disease. Although these are very rare mutations and the disease differs from typical Parkinson's in being very young onset, these genes are interesting in that their loss of function is associated with death of some of the same groups of neurons as in sporadic Parkinson's. The normal function of these genes might therefore tell us something about the ways in which neurons normally protect themselves against damage. Our work has shown that one of these genes, DJ-1, plays a role in protection of cells against oxidative stress by binding to RNA molecules. We know that oxidative damage can modify DJ-1 in a very specific fashion, changing its function and promoting cell survival under conditions where mitochondria are damaged. We are also interested in a mitochondrial kinase, PINK1, and an ubiquitin ligase, parkin, that together represent an alternative pathway for mitochondrial protection. Ongoing work in the laboratory suggests that the kinase activity of PINK1 is critical for preventing stress-induced mitochondrial fragmentation that would otherwise lead to cell death. Our long term goal here is to understand the pathways involved in protecting neurons so that we may be able to harness them to prevent damage in Parkinson's disease.
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Updated: Tuesday April 14, 2015