Cockayne syndrome (CS) is a progressive childhood neurodegenerative disorder associated with a DNA repair defect. Two genes, CSA and CSB, are specifically involved in the CS disorder. These genes are involved in nucleotide excision repair (NER) of ultraviolet damage (UV) in transcriptionally active genes (transcription coupled repair, TCP). Cs-a and Cs-b mice have much milder neurological symptoms than human patients, but a greater risk for cancer that is not usually evident in humans. We have found that crossing Cs-b mice with Xp-c mice, that are defective in NER of nontranscribed regions of the genome, increases the severity and reduces the age of onset of neurodegeneration in animals that are homozygous or heterozygous in both genes but without necessarily compromising UV sensitivity. This has resulted in mouse strains that reflect the range of severity of human CS patients and can be used as models of neurodegeneration that we will compare in detail with the human syndrome. Not all the symptoms of CS patients are however easily related to repair deficiencies, so we hypothesize that there are additional pathways relevant to the disease particularly those that are downstream consequences of a common defect in ubiquitin ligase associated with the CSA and CSB gene products. We have found that the CSB defect results in altered expression of cell cycle and anti-angiogenic genes and proteins, and more programmed cell death that are relevant to the impaired development and progressive neurodegeneration. We therefore propose that, in Aim I, we will determine whether the mouse Cs-b x Xp-c crosses recapitulate the pathology of the human disease. We will determine the specific sites of programmed cell death and whether Purkinje cell loss is a primary event or due to loss of progenitor or associated cell types. We will determine whether neurodegeneration is consistent with premature cell cycle entry and apoptosis from chronic oxidative injury.
In Aim II, we will examine global and transcription coupled repair in human CS cells and mouse fibroblasts from our mouse strains and differentiation-associated repair in mouse cells of neuronal origin following damage from reactive oxygen, to identify the contributions of these repair genes to neurodegeneration.
In Aim III we will determine the roles played by protein targets of CS-dependent ubiquitylation that we have identified, especially those whose over-expression may have pathological consequences. We will emphasize those targets previously identified, such as p21 and collagen 15a1, for their roles in development and neurodegeneration. Successful conclusion of these studies will expand our knowledge of mechanisms of neurodegeneration and lay groundwork for development of therapeutic approaches for CS patients. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052781-02
Application #
7252003
Study Section
Special Emphasis Panel (ZRG1-NDBG-A (09))
Program Officer
Tagle, Danilo A
Project Start
2006-07-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$336,178
Indirect Cost
Name
University of California San Francisco
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Brennan-Minnella, Angela M; Arron, Sarah T; Chou, Kai-Ming et al. (2016) Sources and consequences of oxidative damage from mitochondria and neurotransmitter signaling. Environ Mol Mutagen 57:322-30
Revet, Ingrid; Feeney, Luzviminda; Tang, Amy A et al. (2012) Dysmyelination not demyelination causes neurological symptoms in preweaned mice in a murine model of Cockayne syndrome. Proc Natl Acad Sci U S A 109:4627-32
de Feraudy, Sebastien; Revet, Ingrid; Bezrookove, Vladimir et al. (2010) A minority of foci or pan-nuclear apoptotic staining of gammaH2AX in the S phase after UV damage contain DNA double-strand breaks. Proc Natl Acad Sci U S A 107:6870-5
de Feraudy, Sebastien; Boubakour-Azzouz, Imenne; Fraitag, Sylvie et al. (2010) Diagnosing xeroderma pigmentosum group C by immunohistochemistry. Am J Dermatopathol 32:109-17
Cleaver, James E; Lam, Ernest T; Revet, Ingrid (2009) Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity. Nat Rev Genet 10:756-68
Baure, Jennifer; Izadi, Atefeh; Suarez, Vannina et al. (2009) Histone H2AX phosphorylation in response to changes in chromatin structure induced by altered osmolarity. Mutagenesis 24:161-7
Wakasugi, Mitsuo; Kasashima, Hiromi; Fukase, Yuko et al. (2009) Physical and functional interaction between DDB and XPA in nucleotide excision repair. Nucleic Acids Res 37:516-25
Cleaver, J E; Revet, I (2008) Clinical implications of the basic defects in Cockayne syndrome and xeroderma pigmentosum and the DNA lesions responsible for cancer, neurodegeneration and aging. Mech Ageing Dev 129:492-7
Chen, Yih-Wen; Cleaver, James E; Hatahet, Zafer et al. (2008) Human DNA polymerase eta activity and translocation is regulated by phosphorylation. Proc Natl Acad Sci U S A 105:16578-83
Laposa, Rebecca R; Feeney, Luzviminda; Crowley, Eileen et al. (2007) p53 suppression overwhelms DNA polymerase eta deficiency in determining the cellular UV DNA damage response. DNA Repair (Amst) 6:1794-804

Showing the most recent 10 out of 13 publications