Cockayne syndrome (CS) is a devastating autosomal recessive disease characterized by neurodegeneration, cachexia, and accelerated aging. Previously, we generated a database dedicated to scoring diseases for mitochondrial involvement (www.mitodb.com). Based on the signs and symptoms seen in Cockayne Syndrome (CS) and other DNA repair deficient disorders like Ataxia Telangiectasia (AT) and Xeroderma Pigmentosum group A (XPA), we classified these disorders as likely having a mitochondrial component. In CS cells, there are deficiencies in the repair of oxidative DNA damage in both nuclear and mitochondrial DNA, and this may be a major underlying cause of the disease. Previously, we demonstrated that the CSB protein interacts with PARP1, a protein involved in the early steps of DNA single-strand break repair, and that these two proteins cooperate in the cellular responses to oxidative stress. PARP1 metabolizes NAD+, and consequently, in target tissues like the brain, lower levels of NAD+ may be contributing to mitochondrial dysfunction and CS pathology including its severe early onset neurodegeneration. The clinical presentation of mice carrying a mutation in CSB involves hearing loss, microglial activation, cachexia, and are mild compared to the catastrophic disease phenotype of CS in human patients. Our recent studies revealed novel features in the Csb mouse model, including elevated metabolic rate, altered autophagy and mitophagy, the selective clearance of defective mitochondria. Mitochondrial content is increased in CSB-deficient cells, whereas autophagy is down-regulated. Csb mice are very lean so we tested whether an altered diet may be of benefit. A high fat or caloric restricted diet was delivered to the Csb mice and the high fat diet was of benefit. In contrast, a caloric restrictive diet exacerbated the features of the Csb mouse. These findings lead us to propose that some features of CS may be amenable to interventions that target mitochondrial health. One major goal of our future research on CS is to explore nutraceutical options that may have benefit for CS patients. Specifically, we believe the mitochondrial abnormalities appear to be caused by decreased activation of the NAD+-SIRT1-PGC-1alpha axis triggered by persistent activation of the DNA damage sensor PARP-1. This leads to mitochondrial membrane hyper-polarization, PINK1 cleavage, and defective mitophagy. These findings underscore the importance of mitophagy in promoting a healthy pool of mitochondria and further in preventing neurodegeneration and premature aging. As a part of this project we seek to identify small molecules which can offset mitochondrial dysfunction in DNA repair deficient syndromes. Other independent projects are underway to interrogate why loss of CSA and CSB each cause the same disorder yet the proteins are so different. Multiple model organisms deficient in either CSA or CSB are being employed to define more precisely what unifying traits are responsible for the premature aging CS phenotypes. Expression array analysis suggested that CSA and CSB protein share a number of common pathways and these are being explored with a view to pinpoint more precisely the common point of action of these two proteins.
| Lee, Ju Yeon; Lake, Robert J; Kirk, Jaewon et al. (2017) NAP1L1 accelerates activation and decreases pausing to enhance nucleosome remodeling by CSB. Nucleic Acids Res 45:4696-4707 |
| Fivenson, Elayne M; Lautrup, Sofie; Sun, Nuo et al. (2017) Mitophagy in neurodegeneration and aging. Neurochem Int 109:202-209 |
| Karikkineth, Ajoy C; Scheibye-Knudsen, Morten; Fivenson, Elayne et al. (2017) Cockayne syndrome: Clinical features, model systems and pathways. Ageing Res Rev 33:3-17 |
| Fang, Evandro Fei; Scheibye-Knudsen, Morten; Chua, Katrin F et al. (2016) Nuclear DNA damage signalling to mitochondria in ageing. Nat Rev Mol Cell Biol 17:308-21 |
| Scheibye-Knudsen, Morten; Tseng, Anne; Borch Jensen, Martin et al. (2016) Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA. Proc Natl Acad Sci U S A 113:12502-12507 |
| Scheibye-Knudsen, Morten; Fang, Evandro F; Croteau, Deborah L et al. (2015) Protecting the mitochondrial powerhouse. Trends Cell Biol 25:158-70 |
| Iyama, Teruaki; Lee, Sook Y; Berquist, Brian R et al. (2015) CSB interacts with SNM1A and promotes DNA interstrand crosslink processing. Nucleic Acids Res 43:247-58 |
| Scheibye-Knudsen, Morten; Mitchell, Sarah J; Fang, Evandro F et al. (2014) A high-fat diet and NAD(+) activate Sirt1 to rescue premature aging in cockayne syndrome. Cell Metab 20:840-855 |
| Scheibye-Knudsen, Morten; Fang, Evandro Fei; Croteau, Deborah L et al. (2014) Contribution of defective mitophagy to the neurodegeneration in DNA repair-deficient disorders. Autophagy 10:1468-9 |
| Fang, Evandro Fei; Scheibye-Knudsen, Morten; Brace, Lear E et al. (2014) Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157:882-896 |
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