Cell Biology and Gene Expression Section
Mark R Cookson, Ph.D., Chief
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, although other brain regions are also affected throughout the disease progression. 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. Furthermore, common variation in many genes contributes to risk of sporadic PD. Our work is aimed at using this genetic information to understand the pathways involved that lead to neuronal damage and death. Specifically, we use a range of molecular, cellular and animal models to look at the effects of mutations on proteins and of mutant or missing proteins on cells and on the function of the aging nervous system. We are especially interested in large-scale or unbiased approaches to answer these questions where possible.
- Parkinson's disease
- Familial mutations
- Genome-wide association studies
- Leucine-rich repeat kinase 2
- Vesicular trafficking
- Trans Golgi Network
- Glial cells
- Neuroimmune activation
- Mouse models
- Induced pluripotent stem cells
- High content imaging
- siRNA screening
- Protein interactions
Key Findings and Publications
Chia R, Haddock S, Beilina A, Rudenko IN, Mamais A, Kaganovich A, Li Y, Kumaran R, Nalls MA, Cookson MR. Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7. Nat Commun. 2014 Dec 15;5:5827. doi: 10.1038/ncomms6827.
Beilina A, Rudenko IN, Kaganovich A, Civiero L, Chau H, Kalia SK, Kalia LV, Lobbestael E, Chia R, Ndukwe K, Ding J, Nalls MA; International Parkinson’s Disease Genomics Consortium.; North American Brain Expression Consortium., Olszewski M, Hauser DN, Kumaran R, Lozano AM, Baekelandt V, Greene LE, Taymans JM, Greggio E, Cookson MR. Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease. Proc Natl Acad Sci U S A. 2014 Feb 18;111(7):2626-31. doi: 10.1073/pnas.1318306111. Epub 2014 Feb 7.
McCoy MK, Kaganovich A, Rudenko IN, Ding J, Cookson MR. Hexokinase activity is required for recruitment of parkin to depolarized mitochondria. Hum Mol Genet. 2014 Jan 1;23(1):145-56. doi: 10.1093/hmg/ddt407. Epub 2013 Aug 19.
Soreq L; UK Brain Expression Consortium.; North American Brain Expression Consortium., Rose J, Soreq E, Hardy J, Trabzuni D, Cookson MR, Smith C, Ryten M, Patani R, Ule J. Major shifts in glial regional identity are a transcriptional hallmark of human brain aging. Cell Rep. 2017 Jan 10;18(2):557-570. doi: 10.1016/j.celrep.2016.12.011.
Dillman AA, Hauser DN, Gibbs JR, Nalls MA, McCoy MK, Rudenko IN, Galter D, Cookson MR. mRNA expression, splicing and editing in the embryonic and adult mouse cerebral cortex. Nat Neurosci. 2013 Apr;16(4):499-506. doi: 10.1038/nn.3332. Epub 2013 Feb 17.
Dillman AA, Majounie E, Ding J, Gibbs JR, Hernandez D, Arepalli S, Traynor BJ, Singleton AB, Galter D, Cookson MR. Transcriptomic profiling of the human brain reveals that altered synaptic gene expression is associated with chronological aging.Sci Rep. 2017 Dec 4;7(1):16890. doi: 10.1038/s41598-017-17322-0. PMID: 29203886
Liu Z, Bryant N, Kumaran R, Beilina A, Abeliovich A, Cookson MR, West AB. LRRK2 phosphorylates membrane-bound Rabs and is activated by GTP-bound Rab7L1 to promote recruitment to the trans-Golgi network. Hum Mol Genet. 2018 Jan 15;27(2):385-395.doi: 10.1093/hmg/ddx410. PMID: 29177506
Hauser DN, Mamais A, Conti MM, Primiani CT, Kumaran R, Dillman AA, Langston RG, Beilina A, Garcia JH, Diaz-Ruiz A, Bernier M, Fiesel FC, Hou X, Springer W, Li Y, de Cabo R, Cookson MR.Hexokinases link DJ-1 to the PINK1/parkin pathway. Mol Neurodegener. 2017 Sep 29;12(1):70. doi: 10.1186/s13024-017-0212-x. PMID: 28962651
Blauwendraat C, Francescatto M, Gibbs JR, Jansen IE, Simón-Sánchez J, Hernandez DG, Dillman AA, Singleton AB, Cookson MR, Rizzu P, Heutink P.Comprehensive promoter level expression quantitative trait loci analysis of the human frontal lobe.Genome Med. 2016 Jun 10;8(1):65. doi: 10.1186/s13073-016-0320-1. PMID: 27287230