Evgeny Shlevkov

About

Evgeny Shlevkov, Ph.D., is a cell biologist, neuroscientist and drug hunter. As Assistant Director, Drug Discovery at the Lieber Institute for Brain Development, Evgeny supports in vitro pharmacology and target validation studies. Evgeny is also exploring new approaches to identify druggable cell signaling nodes in schizophrenia and related neurodevelopmental disorders.

Before joining the LIBD, Evgeny served as Head of Neurobiology at Myro Therapeutics, a neuroscience-focused start-up, and led target validation and small molecule screening efforts at Biogen. His team was the first to show that the E3 ligase Parkin can be activated with a small molecule, demonstrating that Parkin is a druggable target.

Evgeny completed his postdoctoral training at Harvard Medical School in the laboratory of Thomas Schwarz, where he established a pioneering high-content screen for modulators of axonal trafficking of mitochondria and identified actives that reversed deficient mitochondrial transport in hiPSC-derived motor neurons from ALS patients. Evgeny received his Ph.D. from Madrid Autonomous University (Spain), where he worked in the laboratory of Gines Morata to dissect components of the apoptotic pathway that promoted the secretion of proliferative ques by dying cells in a phenomenon known as “compensatory proliferation.”

Evgeny is a recipient of the Parkinson’s Disease Foundation Postdoctoral Fellowship, the Madrid Autonomous University Introduction Into Research Award and the Fellowship for the Training of University Professors by the Spanish Ministry of Education and Science.

Research

Drug discovery requires the development of accurate cellular models to validate, triage and understand the mechanism of action of future therapeutics. Cellular models range from heterologous systems with overexpressed targets of interest to neurons derived from human-induced pluripotent stem cells. Each model has its unique advantages and disadvantages, and therefore a comprehensive drug discovery program requires the use of as many cellular models as possible in order to identify the most promising candidates for further development. Evgeny’s group is focused on designing and developing robust cell-based models and assays to support drug discovery programs at the LIBD.

The molecular biology of schizophrenia and related neurodevelopmental disorders remains poorly understood. Dysfunctions in several key neurotransmitter systems have been identified, mainly thanks to pharmacological and genetic studies, but how such dysfunctions arise and develop in the first place is unclear. Transcriptomic studies from postmortem brains point toward cellular pathways that may underlie the progression of the disorder. Evgeny’s group is using advanced molecular and cell biology techniques to test novel hypotheses emerging from post-mortem brain studies with the goal of understanding the molecular mechanisms driving the progression of neurodevelopmental disorders.

Finally, leveraging concepts from systems biology, the group aims at constructing genotype-phenotype-drug response associations with the goal of understanding molecular underpinnings underlying patient-to-patient variability in drug response and therapeutic efficacy. Such an integrative approach, by combining small-molecule screening, cell phenotyping and patient-derived hiPSC technology, has the potential to identify novel druggable cell signaling nodes in schizophrenia and related neurodevelopmental disorders.

Team Members

Daming Chen, PhD (Staff Scientist I)

Gangling Liao, PhD (Staff Scientist I)

Frank Piscotta, PhD (Staff Scientist I)

Selected Publications

Heo K., Basu H., Gutnick A., Wei W., Shlevkov E., Schwarz T. Serine/Threonine Protein Phosphatase 2A Regulates the Transport of Axonal Mitochondria. Front Cell Neurosci (2022) Mar 18;16:852245

Shlevkov E., Murugan P., Montagna D., Stefan E., Hadzipasic A., et al. Discovery of small-molecule positive allosteric modulators of Parkin E3 ligase. iScience (2021) Dec 18; 25(1):103650

Apicco D., Shlevkov E., Guilmette E., Nicholatos E., Nezich C., et al. The Parkinson’s disease associated gene ITPKB protects against α-synuclein aggregation by inhibiting ER-to-mitochondria calcium release. PNAS (2021) 118 (1) e2006476118

Bantle C., Weihofen A., Hirst W., Shlevkov E. Mitochondrial dysfunction in astrocytes: role in Parkinson’s disease? Frontiers in Cell and Developmental Biology (2021) 8, 1587

Shlevkov E., Basu H., Bray MA., Sun Z., Wei Wei et al. High-Content Screen Identifies TPP1 and Aurora B as Regulators of Axonal Mitochondrial Trafficking. Cell Reports (2019); ISSN: 2211-1247, Vol:28, Issue:12, Page: 3224-3237. e5

Shlevkov E., Schwarz T.L., Axonal transport of mitochondria and Parkinson’s Disease (2017) Chapter 4 in Mechanisms of Parkinson’s Disease ed. P. Verstreken.

Shlevkov E., Kramer T., Schapansky J., LaVoie M., Schwarz T.L. Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility. PNAS (2016); doi: 10.1073/pnas.1612283113

Shlevkov E. and Morata G. A dp53/JNK-dependent feedback amplification loop is essential for the apoptotic response to stress in Drosophila. Cell Death Differ (2012); Mar 19(3):451-60