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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 variations in many genes contributes to risk of sporadic Parkinson’s disease.
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 variants 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.
Portfolio/Research Areas
- Parkinson's disease
- Genome-wide association studies
- Leucine-rich repeat kinase 2
- Alpha-synuclein
- DJ-1
- PINK1
- Parkin
- Vesicular trafficking
- Lysosomes
- Neurons
- Glial cells
- Neuroimmune activation
- Aging
- Mouse models
- Induced pluripotent stem cells
- CRISPR/Cas editing
- siRNA screening
- Proteomics
- Protein interactions
- RNA-Seq
Key Findings and Publications
Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, Kaganovich A, van der Brug MP, Beilina A, Blackinton J, Thomas KJ, Ahmad R, Miller DW, Kesavapany S, Singleton A, Lees A, Harvey RJ, Harvey K, Cookson MR. Kinase activity is required for the toxic effects of mutant LRRK2/dardarin . Neurobiol Dis. 2006 Aug;23(2):329-41. doi: 10.1016/j.nbd.2006.04.001. Epub 2006 Jun 5. PMID: 16750377.
Lewis PA, Greggio E, Beilina A, Jain S, Baker A, Cookson MR. The R1441C mutation of LRRK2 disrupts GTP hydrolysis . Biochem Biophys Res Commun. 2007 Jun 8;357(3):668-71. doi: 10.1016/j.bbrc.2007.04.006. Epub 2007 Apr 10. PMID: 17442267; PMCID: PMC1939973.
Greggio E, Zambrano I, Kaganovich A, Beilina A, Taymans JM, Daniëls V, Lewis P, Jain S, Ding J, Syed A, Thomas KJ, Baekelandt V, Cookson MR. The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation . J Biol Chem. 2008 Jun 13;283(24):16906-14. doi: 10.1074/jbc.M708718200. Epub 2008 Apr 8. PMID: 18397888; PMCID: PMC2423262.
Thomas KJ, McCoy MK, Blackinton J, Beilina A, van der Brug M, Sandebring A, Miller D, Maric D, Cedazo-Minguez A, Cookson MR. DJ-1 acts in parallel to the PINK1/parkin pathway to control mitochondrial function and autophagy . Hum Mol Genet. 2011 Jan 1;20(1):40-50. doi: 10.1093/hmg/ddq430. Epub 2010 Oct 11. PMID: 20940149; PMCID: PMC3000675.
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 USA. 2014 Feb 18;111(7):2626-31. doi: 10.1073/pnas.1318306111. Epub 2014 Feb 7. PMID: 24510904; PMCID: PMC3932908.
Bonet-Ponce L, Beilina A, Williamson CD, Lindberg E, Kluss JH, Saez-Atienzar S, Landeck N, Kumaran R, Mamais A, Bleck CKE, Li Y, Cookson MR. LRRK2 mediates tubulation and vesicle sorting from lysosomes . Sci Adv. 2020 Nov 11;6(46):eabb2454. doi: 10.1126/sciadv.abb2454. PMID: 33177079; PMCID: PMC7673727.
Langston RG, Beilina A, Reed X, Kaganovich A, Singleton AB, Blauwendraat C, Gibbs JR, Cookson MR. Association of a common genetic variant with Parkinson's disease is mediated by microglia . Sci Transl Med. 2022 Jul 27;14(655):eabp8869. doi: 10.1126/scitranslmed.abp8869. Epub 2022 Jul 27. PMID: 35895835; PMCID: PMC9809150.
Pantazis CB, Yang A, Lara E, McDonough JA, Blauwendraat C, Peng L, Oguro H, Kanaujiya J, Zou J, Sebesta D, Pratt G, Cross E, Blockwick J, Buxton P, Kinner-Bibeau L, Medura C, Tompkins C, Hughes S, Santiana M, Faghri F, Nalls MA, Vitale D, Ballard S, Qi YA, Ramos DM, Anderson KM, Stadler J, Narayan P, Papademetriou J, Reilly L, Nelson MP, Aggarwal S, Rosen LU, Kirwan P, Pisupati V, Coon SL, Scholz SW, Priebe T, Öttl M, Dong J, Meijer M, Janssen LJM, Lourenco VS, van der Kant R, Crusius D, Paquet D, Raulin AC, Bu G, Held A, Wainger BJ, Gabriele RMC, Casey JM, Wray S, Abu-Bonsrah D, Parish CL, Beccari MS, Cleveland DW, Li E, Rose IVL, Kampmann M, Calatayud Aristoy C, Verstreken P, Heinrich L, Chen MY, Schüle B, Dou D, Holzbaur ELF, Zanellati MC, Basundra R, Deshmukh M, Cohen S, Khanna R, Raman M, Nevin ZS, Matia M, Van Lent J, Timmerman V, Conklin BR, Johnson Chase K, Zhang K, Funes S, Bosco DA, Erlebach L, Welzer M, Kronenberg-Versteeg D, Lyu G, Arenas E, Coccia E, Sarrafha L, Ahfeldt T, Marioni JC, Skarnes WC, Cookson MR, Ward ME, Merkle FT. A reference human induced pluripotent stem cell line for large-scale collaborative studies. Cell Stem Cell. 2022 Dec 1;29(12):1685-1702.e22. doi: 10.1016/j.stem.2022.11.004. PMID: 36459969; PMCID: PMC9782786.
Bonet-Ponce L, Tegicho T, Fernandez-Martinez N, Rozenberg IA, Ashriem M, Beilina A, Kluss JH, Li Y, Cookson MR. JIP4 and RILPL1 utilize opposing motor force to dynamically regulate lysosomal tubulation . J Cell Biol. 2025 Nov 3;224(11):e202404018. doi: 10.1083/jcb.202404018. Epub 2025 Sep 24. PMID: 40990465; PMCID: PMC12459091.