Faculty

Kelvin C Luk, PhD

faculty photo
Research Associate Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine
Graduate Group Affiliations

Contact information
3600 Spruce St
1 Maloney Building
HUP
Philadelphia, PA 19104
Office: 215-615-3202
Fax: 215-615-3206
Lab: 215-662-3292
Education:
BSc (Microbiology and Immunology)
McGill University, 1997.
PhD (Pathology)
McGill University, 2004.
MTR (Translational Research)
University of Pennsylvania, 2013.
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Description of Research Expertise

My 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. Lewy bodies are also found in nearly half of all Alzheimer's disease patients examined at autopsy.

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 Publications

Wu Q, Shaikh MA, Meymand ES, Zhang B, Luk KC, Trojanowski JQ, Lee VM: Neuronal activity modulates alpha-synuclein aggregation and spreading in organotypic brain slice cultures and in vivo. Acta Neuropathologica Dec 2020 Notes: doi: 10.1007/s00401-020-02227-6.

Darwich NF, Phan JM, Kim B, Suh E, Papatriantafyllou JD, Changolkar L, Nguyen AT, O'Rourke CM, He Z, Porta S, Gibbons GS, Luk KC, Papageorgiou SG, Grossman M, Massimo L, Irwin DJ, McMillan CT, Nasrallah IM, Toro C, Aguirre GK, Van Deerlin VM, Lee EB: Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau. Science Nov 2020 Notes: doi: 10.1126/science.aay8826.

Kulkarni AS, Del Mar Cortijo M, Roberts ER, Suggs TL, Stover HB, Pena-Bravo JI, Steiner JA, Luk KC, Brundin P, Wesson DW: Perturbation of in vivo Neural Activity Following α-Synuclein Seeding in the Olfactory Bulb. Journal of Parkinsons Disease Sep 2020 Notes: doi: 10.3233/JPD-202241.

Chmielarz P, Er Ş, Konovalova J, Bandres L, Hlushchuk I, Albert K, Panhelainen A, Luk K, Airavaara M, Domanskyi A: GDNF/RET Signaling Pathway Activation Eliminates Lewy Body Pathology in Midbrain Dopamine Neurons. Movement Disorders Page: doi: 10.1002/mds.28258, Sept 2020.

Caputo A, Liang Y, Raabe TD, Lo A, Horvath M, Zhang B, Brown HJ, Stieber A, Luk KC: Snca-GFP knock-in mice reflect patterns of endogenous expression and pathological seeding. eNeuro Aug 2020 Notes: doi: 10.1523/ENEURO.0007-20.2020.

Hoban DB, Shrigley S, Mattsson B, Breger LS, Jarl U, Cardoso T, Nelander Wahlestedt J, Luk KC, Björklund A, Parmar M: Impact of α-synuclein pathology on transplanted hESC-derived dopaminergic neurons in a humanized α-synuclein rat model of PD. PNAS Jun 2020 Notes: doi: 10.1073/pnas.2001305117.

Gezer AO, Kochmanski J, VanOeveren SE, Cole-Strauss A, Kemp CJ, Patterson JR, Miller KM, Kuhn NC, Herman DE, McIntire A, Lipton JW, Luk KC, Fleming SM, Sortwell CE, Bernstein AI: Developmental exposure to the organochlorine pesticide dieldrin causes male-specific exacerbation of α-synuclein-preformed fibril-induced toxicity and motor deficits. Neurobiology of Disease May 2020 Notes: doi: 10.1016/j.nbd.2020.104947.

Henderson 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 alpha-synuclein antibodies as potential immunotherapeutic agents for Parkinson's disease. Neurobiology of Disease 136: https://doi.org/10.1016/j.nbd.2019.104712, Dec 2019.

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.

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.

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Last updated: 11/21/2020
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