Kelvin C Luk, PhD
1 Maloney Building
Philadelphia, PA 19104
BSc (Microbiology and Immunology)
McGill University, 1997.
McGill University, 2004.
MTR (Translational Research)
University of Pennsylvania, 2013.
Description of Research ExpertiseMy research aims to improve our understanding of the synucleinopathies, a group of neurodegenerative disorders that include Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). PD is a progressive neurodegenerative condition that affects over 1 million individuals in the U.S. alone, and for which there is currently no cure.
Our lab's current efforts focus on three major themes:
1) The Role of Protein Misfolding in PD and Related Synucleinopathies: Histopathological, genetic, and experimental evidence suggest that the aggregation and accumulation of alpha-synuclein (α-Syn), the primary component of Lewy bodies, underlies the symptoms seen in PD. We previously demonstrated that aggregated forms of α-Syn are transmissible entities that propagate and spread throughout the brain in a manner akin to prion diseases. This exciting discovery represents a significant shift in our understanding of PD etiology and progression. Through the development of novel biophysical, cell-based and animal models, my work seeks to identify factors that a) regulate α-Syn expression and misfolding, b) determine its route of transmission and c) modulate the toxicity of α-Syn pathology.
2) Novel Therapeutics Against Synucleinopathies: Present PD treatments provide temporary relief to motor impairments but do not alter the neurodegenerative process. In collaboration with UPenn’s Center for Neurodegenerative Disease Research Drug Discovery group, our team has been developing high-throughput screening assays to identify small molecules and biologicals that inhibit the accumulation and transmission of abnormal α-syn species or neutralize their action.
3) Biology of Midbrain Dopamine Neurons: PD is primarily a movement disorder that results from the loss of dopamine-producing neurons in the midbrain. The reasons why this subpopulation is particularly vulnerable in PD is unclear. By characterizing the pathways that govern their development and maintenance, we and others have shown that a susceptible dopamine cells are defined by specific transcription factors that regulate their survival in adulthood. More recently, we have also examined the mechanisms underlying the selective vulnerability in other non-dopamine neuron subpopulations.
This research is conducted by a talented and dedicated team of research specialists, postdoctoral researchers, and students. We are regularly in search of new members.
Selected PublicationsHenderson MX; Covell DJ; Chung CH; Pitkin RM; Sandler RM; Decker SC; Riddle DM; Zhang B; Gathagan RJ; James MJ; Trojanowski JQ; Brunden KR; Lee VMY; Luk KC: Characterization of novel conformation-selective
Chu Y, Muller S, Tavares A, Barret O, Alagille D, Seibyl J, Tamagan G, Marek K, Luk KC, Trojanowski JQ, Lee VMY, Kordower JH: Intrastriatal Alpha-Synuclein Fibrils in Monkeys: Spreading, Imaging and Neuropathologic Changes Brain Oct 2019.
Patterson JR, Duffy MF, Kemp CJ, Howe JW, Collier TJ, Stoll AC, Miller KM, Patel P, Levine N, Moore DJ, Luk KC, Fleming SM, Kanaan NM, Paumier KL, El-Agnaf OMA, Sortwell CE: Time course and magnitude of alpha-synuclein inclusion formation and nigrostriatal degeneration in the rat model of synucleinopathy triggered by intrastriatal α-synuclein preformed fibrils. Neurobiology of Disease 130: 104525, Oct 2019.
Uemura N, Uemura MT, Lo A, Bassil F, Zhang B, Luk KC, Lee VM, Takahashi R, Trojanowski JQ: Slow Progressive Accumulation of Oligodendroglial Alpha-Synuclein (α-Syn) Pathology in Synthetic α-Syn Fibril-Induced Mouse Models of Synucleinopathy. J Neuropathol Exp Neurol 78(10): 877-890, Oct 2019.
Luk KC: Oxidative stress and α-synuclein conspire in vulnerable neurons to promote Parkinson's disease progression. Journal of Clinical Investigation 130, Aug 2019.
Espa E, Clemensson EKH, Luk KC, Heuer A, Björklund T, Cenci MA: Seeding of protein aggregation causes cognitive impairment in rat model of cortical synucleinopathy. Movement Disorders Aug 2019.
Schaser AJ, Osterberg VR, Dent SE, Stackhouse TL, Wakeham CM, Boutros SW, Weston LJ, Owen N, Weissman TA, Luna E, Raber J, Luk KC, McCullough AK, Woltjer RL, Unni VK: Alpha-synuclein is a DNA binding protein that modulates DNA repair with implications for Lewy body disorders. Scientific reports 9(1): 10919, Jul 2019.
Patterson JR, Polinski NK, Duffy MF, Kemp CJ, Luk KC, Volpicelli-Daley LA, Kanaan NM, Sortwell CE: Generation of Alpha-Synuclein Preformed Fibrils from Monomers and Use In Vivo. Journal of visualized experiments : JoVE(148), Jun 2019.
Mason DM, Wang Y, Bhatia TN, Miner KM, Trbojevic SA, Stolz JF, Luk KC, Leak RK: The center of olfactory bulb-seeded α-synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice. Brain pathology Mar 2019.
Zhang B, Kehm V, Gathagan R, Leight SN, Trojanowski JQ, Lee VM-Y, Luk KC: Stereotaxic Targeting of Alpha-Synuclein Pathology in Mouse Brain Using Preformed Fibrils. Methods in Molecular Biology. Springer, 1948: 45-57, Feb 2019.