| Autor: |
Bernd J. Pichler, Janice Stricker-Shaver, Carsten Calaminus, Huu Phuc Nguyen, Benedikt Fabry, Olaf Riess, Lamya S. Shihabuddin, Libo Yu-Taeger, Elisabeth Singer, Lisa M. Stanek |
| Rok vydání: |
2018 |
| Předmět: |
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| Zdroj: |
Pathogenic mechanisms. |
| Popis: |
Background In Huntington disease (HD), the negative impacts of metabolic dysfunctions heavily affects the quality of life of patients. As energy metabolism is centrally regulated by the hypothalamus via a number of proteins, we hypothesize that mutant huntingtin (mHTT) disrupts selective proteins resulting in metabolic disturbances. Aims To investigate disruptions of energy metabolism caused by mHTT in the hypothalamus. Methods A viral-mediated microRNA that could downregulate both wild-type and mutant HTT was administered to the hypothalamus of BACHD rats using bilateral stereotaxic injections. To compare the effects of mHTT downregulation at the time of intervention, BACHD rats were treated at 1 and 6 months of age, which correspond to the early disease and symptomatic stages respectively. Wild-type littermates treated with vector formulation buffer and BACHD rats treated with an empty vector were included as control groups. Brain tissues were harvested 5 months post-treatment for protein analyses. Results Our findings showed that, protein expressions of neuropeptide Y receptor 5 (NPY5R), orexin receptor 1 (OX1R) and leptin receptor were significantly altered in at least one of the disease stages in the hypothalamus of the empty vector-treated BACHD rats when compared to the wild-type littermates. Downregulation of mHTT in the hypothalamus restored the protein expressions of NPY5R, OX1R and leptin receptor in the hypothalamus to respective levels as in the wild-type littermates. Conclusions The physiological functions of the hypothalamus are disrupted by mHTT in HD. Nevertheless, mHTT suppression in the hypothalamus can be an effective approach for restoring the perturbed neuroendocrine axes regulating energy metabolism. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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