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.
Laposa RR, Huang EJ, Cleaver JE. Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice. Proc Natl Acad Sci USA. 2007; 104(4):1389-94.
Laposa RR , Feeney L, Crowley E, de Feraudy S, Cleaver JE. p53 suppression overwhelms DNA polymerase eta deficiency in determining the cellular UV DNA damage response. DNA Repair (Amst). 2007; 6(12):1794-804.
Cleaver JE, Hefner E, Laposa RR, Karentz D, Marti T. Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair. Neuroscience. 2007; 45(4):1300-8.
Laposa RR, Henderson JT, Xu E and Wells PG. Atm-null mice exhibit enhanced radiation-induced birth defects and a hybrid form of embryonic programmed cell death indicating a teratological suppressor function for ATM. FASEB J. 2004; 18(7):896-84.
Laposa RR, Feeney L and Cleaver JE. Recapitulation of the cellular xeroderma pigmentosum-variant phenotypes using short interfering RNA for DNA polymerase H. Cancer Res. 2003; 63(14):3909-12.
Laposa RR, Henderson JT and Wells PG. Tetracycline-dependent regulation of formamidopyrimidine DNA glycosylase in transgenic mice conditionally reduces oxidative DNA damage in vivo. FASEB J. 2003; 17(10):1343-5.
Laposa RR and Cleaver, JE. DNA Repair on the brain. Proc Natl Acad Sci USA. 2001 98:12860-12862.
Department of Pharmacology and Toxicology
Room 4212, Medical Sciences Building
1 King's College Circle