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Kostantin Dobrenis, Ph.D.

Kostantin Dobrenis, Ph.D.

Associate Professor, Dominick P. Purpura Department of Neuroscience

Contact Information

718.430.2162718.430.8821kostantin.dobrenis@einsteinmed.edu

Albert Einstein College of Medicine
Rose F. Kennedy Center
1410 Pelham Parkway South, Room 618
Bronx, NY 10461

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Professional Interests

Our principal interests lie in the pathogenesis and therapy of neurodegenerative diseases, and in the fields of ganglioside and microglial biology. We have contributed to the characterization of animal models of neuronal lysosomal storage diseases including Tay-Sachs/Sandhoff disease, Niemann Pick C (NPC) disease, mucopolysaccharidosis (MPS) IIIA, and mucolipidosis IV, and more recently to understanding the pathogenesis of Christianson Syndrome, a sodium/hydrogen exchanger deficiency that displays features of storage disorders. Much of our work has been directed at developing rational therapeutic strategies for these and related genetic diseases which affect the central nervous system (CNS) in a global manner. The goal here is to find ways to effectively replace the missing protein, or compensate for its function, within cells throughout the CNS. This entails overcoming challenges such as the blood brain barrier, and developing strategies that enhance neuronal uptake of therapeutic compounds. One of our ongoing projects in this regard is the development of fusion genes of hexosaminidase, the enzyme deficient in Tay Sachs disease, and peptide sequences related to the atoxic fragment of tetanus toxin. Due to charaacteristics of the latter, the encoded chimeric proteins have properties allowing circumvention of the blood brain barrier, increased neuronal endocytotic uptake into the lysosomal compartment, and transneuronal transsynaptic trafficking for wider dissemination of the needed protein. Additional projects include: exploring the efficacy and delineating the mechanisms of action of small molecule therapies such as miglustat, related analogs, and cyclodextrin for storage diseases, now seeing human application, in cellular, biochemical, gene expression and behavioral assays; and investigation of novel contact-mediated mechanisms of neuronal-microglial lysosomal enzyme transfer for effective hematopoietic stem cell replacement CNS therapy. Furthermore we continue to be engaged in studies examining the role and expression patterns of gangliosides and microglia in development and neuropathology. The lab utilizes techniques ranging from molecular recombinant work to animal behavioral assays with extensive experience in: cell culture preparations of all the major CNS cell types; gangliosides and lysosomal enzyme biochemistry; vital and fixed specimen histologic and immunocytochemical techniques; modern fluorescent techniques for monitoring organellar or biochemical activities in living cells; and a wide range of high resolution imaging and image analysis techniques.

Selected Publications

Boudewyn, L.C., Sikora, J., Kuchar, L., Ledvinova, J., Grishchuk, Y., Wang, S., Dobrenis, K., Walkley, S.U. N-butyl-deoxynojirimycin delays motor deficits, cerebellar microgliosis and Purkinje cell loss in a mouse model of mucolipidosis type IV. Neurobiol. Disease, 105:257-270, 2017.

Trilck, M., Peter, F., Zheng, C., Frank, M., Dobrenis, K., Mascher, H., Rolfs, A., Frech, M.J. Diversity of glycosphingolipid GM2 and cholesterol accumulation in NPC1 patient-specific iPSC-derived neurons. Brain Res. 1657:52-61, 2017.

Yang, D.-S., Stavrides, P., Kumar, K., Jiang, Y, Mohan, PS., Ohno, M., Dobrenis, K., Davidson, C.D., Saito, M, Pawlik, M., Huo, C., Walkley, S.U., Nixon, R.A. Cyclodextrin has conflicting actions on autophagy flux in vivo in brains of normal and Alzheimer model mice. Human Mole. Genet. 26:843-859, 2017.

Davidson, C., Fishman, YI, Puskas I., Szeman, J., Sohajda, T., McCauliff, L.A., Sikora, J., Storch, J., Vanier M.T., Szente, L., Walkley, S.U., Dobrenis, K. Efficacy and ototoxicity of different cyclodextrins in Niemann-Pick C disease. Ann Clin Transl Neurol. 3:366-380, 2016.

Saito, M., Wu, G., Hui, M., Masiello, K., Dobrenis, K., Ledeen, R.W., Saito, M. Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNacT KO mice. J. Lipid Res. 56:1434-1448, 2015.

Farfel-Becker, T., Vitner, E.B., Kelly, S.L., Bame, J.R., Duan, J., Shinder, V., Merrill Jr, A.F., Dobrenis, K., Futerman, A.H. Neuronal accumulation of glucosylceramide in a mouse model of neuronopathic Gaucher disease leads to neurodegeneration. Human Molec. Genet 23:843-854, 2014.

Micsenyi, M.C., Sikora, J., Stephney, G., Dobrenis, K., Walkley, S.U. Lysosomal membrane permeability stimulates protein aggregate formation in neurons of a lysosomal disease. J. Neurosci. 33:10815-10827, 2013.

Erblich, B., Zhu, L., Etgen, A., Dobrenis, K., Pollard, J.W. Absence of colony stimulating factor-1 receptor signaling results in loss of microglia, disrupted brain development and olfactory deficits. PloS One, 2011. 2011;6(10):e26317. Epub 2011 Oct 27.

Stromme, P., Dobrenis, K., Sillitoe, R.V., Gulinello, M., Ali, N.F., Davidson, C., Micsenyi, M.C., Stephney, G., Ellevog, L., Klunglund, A., Walkley, S.U. X-linked Angelman-like syndrome caused by Slc9a6 knockout in mice exhibits evidence of endosomal-lysosomal dysfunction. Brain 134:3369-83, 2011.

Gulinello, M., Chen, F., Dobrenis, K. Early deficits in motor coordination, cognitive function and anxiety-like behavior in a mouse model of the neurodegenerative lysosomal storage disorder, Sandhoff disease. Behav. Brain Res. 193:315-319, 2008.