Faculty: Rebecca Laposa, PhD
Coordinator, PEY Internship Program
General Area of Research: Toxicology, Neuropharmacology, Biochemical & Molecular Pharmacology
DNA Damage and Repair in Neurodegeneration and Neural Stem Cells
Within the research area of molecular toxicology, my specific interest and expertise lies in the role that DNA repair and DNA replication of endogenous and environmentally induced DNA damage play in diseases of the central nervous system. Cells of the human body are continuously exposed to agents that damage their DNA; this damage can lead to altered transcription of genes and, in dividing cells, permanent genetic alterations. For genotoxic compounds, cells possess defense mechanisms that include networks of DNA damage response proteins along with enzymes that directly repair or replicate damaged DNA. While DNA damage and its related cellular stress response and repair systems have long been studied with respect to cancer, their importance in neurodegenerative disease has only recently become appreciated. DNA damage appears to contribute to neurodegeneration.
Neural stem and progenitor cells play an essential role in both the developing embryonic and the adult nervous systems where the capacity for self-renewal and proliferation may be important for the normal function of the CNS, such as in learning and memory, as well as in the response to injury. Neural stem and progenitor cells possess DNA damage responses and utilize DNA repair mechanisms that are dramatically and unpredictably different from those in other cell types in the brain and elsewhere. Moreover, these cells are exquisitely sensitive to certain DNA-damaging agents. An emerging area of research is beginning to examine the particular role of neural stem cells, and damage to mitochondrial as distinct from nuclear DNA, in the molecular mechanism of neurodegeneration. DNA repair is a potential risk factor under study in my laboratory.
Liyanage SU, Hurren R, Voisin V, Bridon G, Wang X, Xu C, MacLean N, Siriwardena TP, Gronda M, Yehudai D, Sriskanthadevan S, Avizonis D, Shamas-Din A, Minden MD, Bader GD, Laposa R, Schimmer AD. Leveraging increased cytoplasmic nucleoside kinase activity to target mtDNA and oxidative phosphorylation in AML. Blood 2017 Mar 10.
Wang Y, Jones-Tabah J, Chakravarty P, Stewart A, Muotri A, Laposa RR, Svejstrup JQ.Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation. Cell Rep. 2016 Mar 22;14(11):2554-61.
Bralha FN, Liyanage SU, Hurren R, Wang X, Son MH, Fung TA, Chingcuanco FB, Tung AY, Andreazza AC, Psarianos P, Schimmer AD, Salmena L, Laposa RR. Targeting mitochondrial RNA polymerase in acute myeloid leukemia.Oncotarget. 2015 Nov 10;6(35):37216-28.
Yeung M, Hurren R, Nemr C, Wang X, Hershenfeld S, Gronda M, Liyanage S, Wu Y, Augustine J, Lee EA, Spagnuolo PA, Southall N, Chen C, Zheng W, Jeyaraju DV, Minden MD, Laposa R, Schimmer AD. Mitochondrial DNA damage by bleomycin induces AML cell death. Apoptosis. 2015 Jun;20(6):811-20.
Wisnovsky SP, Wilson JJ, Radford RJ, Pereira MP, Chan MR, Laposa RR, Lippard SJ, Kelley SO. Targeting mitochondrial DNA with a platinum-based anticancer agent. 2013. Chemistry & Biology. 20(11):1323-8
Sacco, R., Tamblyn, L., Rajakulendran, N., Bralha, F.N., Tropepe, V. and Laposa, R.R. Cockayne syndrome b maintains neural precursor function. 2013. DNA Repair 12(2): 110-20.
Wong, J.C., Visanji, N.P., Dabek , M.K., Laposa, R.R. and Hazrati, L.-N. Altered dendritic spine density and morphology in a mouse model of Cockayne syndrome. 2013. Neuropathology and Applied Neurobiology. 39(4):437-40.
Ogawa S, Surapisitchat J, Virtanen C, Ogawa M, Niapour M, Sugamori KS, Wang S, Tamblyn L, Guillemette C, Hoffmann E, Zhao B, Strom S, Laposa RR, Tyndale RF, Grant DM, Keller G. Three-dimensional culture and cAMP signaling promote the maturation of human pluripotent stem cell-derived hepatocytes. 2013. Development 140(15):3285-96.
Department of Pharmacology and Toxicology
Room 4212, Medical Sciences Building
1 King's College Circle