| Full text | |
| Author(s): Show less - |
Kajitani, Gustavo Satoru
[1, 2]
;
Brace, Lear
[2]
;
Trevino-Villarreal, Jose Humberto
[2]
;
Trocha, Kaspar
[2]
;
MacArthur, Michael Robert
[2, 3]
;
Vose, Sarah
[2]
;
Vargas, Dorathy
[4]
;
Bronson, Roderick
[4]
;
Mitchell, Sarah Jayne
[2, 3]
;
Martins Menck, Carlos Frederico
[1]
;
Mitchell, James Robert
[2, 3]
Total Authors: 11
|
| Affiliation: | [1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Microbiol, Sao Paulo - Brazil
[2] Harvard Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 - USA
[3] Swiss Fed Inst Technol, Dept Hlth Sci & Technol, Zurich - Switzerland
[4] Harvard Med Sch, Dept Pathol, Rodent Histopathol Core, Boston, MA 02115 - USA
Total Affiliations: 4
|
| Document type: | Journal article |
| Source: | AGING-US; v. 13, n. 19, p. 22710-22731, OCT 15 2021. |
| Web of Science Citations: | 0 |
| Abstract | |
Cockayne syndrome (CS) is a rare, autosomal genetic disorder characterized by premature aging-like features, such as cachectic dwarfism, retinal atrophy, and progressive neurodegeneration. The molecular defect in CS lies in genes associated with the transcription-coupled branch of the nucleotide excision DNA repair (NER) pathway, though it is not yet clear how DNA repair deficiency leads to the multiorgan dysfunction symptoms of CS. In this work, we used a mouse model of severe CS with complete loss of NER (Csa(-/-)/Xpa(-/-)), which recapitulates several CS-related phenotypes, resulting in premature death of these mice at approximately 20 weeks of age. Although this CS model exhibits a severe progeroid phenotype, we found no evidence of in vitro endothelial cell dysfunction, as assessed by measuring population doubling time, migration capacity, and ICAM-1 expression. Furthermore, aortas from CX mice did not exhibit early senescence nor reduced angiogenesis capacity. Despite these observations, CX mice presented blood brain barrier disruption and increased senescence of brain endothelial cells. This was accompanied by an upregulation of inflammatory markers in the brains of CX mice, such as ICAM-1, TNF alpha, p-p65, and glial cell activation. Inhibition of neovascularization did not exacerbate neither astro-nor microgliosis, suggesting that the pro-inflammatory phenotype is independent of the neurovascular dysfunction present in CX mice. These findings have implications for the etiology of this disease and could contribute to the study of novel therapeutic targets for treating Cockayne syndrome patients. (AU) | |
| FAPESP's process: | 19/19435-3 - The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing (DNA MoVINg) |
| Grantee: | Carlos Frederico Martins Menck |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center |
| Grantee: | Mayana Zatz |
| Support Opportunities: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |