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| Content Provider | Springer Nature Link |
|---|---|
| Author | Kirshner, Michal Galron, Ronit Frenkel, Dan Mandelbaum, Gil Shiloh, Yosef Wang, Zhao Qi Barzilai, Ari |
| Copyright Year | 2011 |
| Abstract | Pronounced neuropathology is a feature of ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS), which are both genomic instability syndromes. The Nbs1 protein, which is defective in NBS, is a component of the Mre11/RAD50/NBS1 (MRN) complex. This complex plays a major role in the early phase of the cellular response to double strand breaks (DSBs) in the DNA. Among others, MRN is required for timely activation of the protein kinase ATM (A-T mutated), which is disrupted in patients with A-T. Earlier reports show that Atm-deficient mice exhibit severe degeneration of tyrosine hydroxylase (TH)-positive dopaminergic nigro-striatal neurons and their terminals in the striatum. This cell loss is accompanied by a large reduction in immunoreactivity for the dopamine transporter protein (DAT) in the striatum. To test whether Nbs1 inactivation also affects the integrity of the nigro-striatal pathway, we examined this pathway in a murine model with conditional inactivation of the Nbs1 gene in central nervous system (Nbs1-CNS-Δ). We report that this model has a reduction in TH-positive cells in the substantia nigra. This phenomenon was seen at very early age, while Atm−/− mice showed a progressive age-dependent reduction. Furthermore, we observed an age-dependent increase in the level of TH in the striatum of Atm−/− and Nbs1-CNS-Δ mice. In addition to the altered expression of TH, we also found a reduction of DAT in the striatum of both Atm−/− and Nbs1-CNS-Δ mice at 60 days of age. Finally, microglial recruitment and alterations in the levels of various neurotrophic factors were also observed. These results indicate that malfunctioning DNA damage response severely affects the integrity of the nigro-striatal pathway and suggest a new neurodegenerative pathway in Parkinsonian syndromes. |
| Starting Page | 554 |
| Ending Page | 568 |
| Page Count | 15 |
| File Format | |
| ISSN | 08958696 |
| Journal | Journal of Molecular Neuroscience |
| Volume Number | 46 |
| Issue Number | 3 |
| e-ISSN | 15591166 |
| Language | English |
| Publisher | Humana Press Inc |
| Publisher Date | 2011-09-16 |
| Publisher Place | New York |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Ataxia-telangiectasia Nijmegen breakage syndrome Atm Nbs1 DNA damage response Nigro-striatal pathway Dopaminergic neurons Glial cells Neurology Cell Biology Neurochemistry Proteomics Neurosciences |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Cellular and Molecular Neuroscience |
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