HDAC6 dysfunction contributes to impaired maturation of adult neurogenesis in vivo: vital role on functional recovery after ischemic stroke
| Autor: | Cheng-Ying Hsieh, Shin-Wei Huang, Thanasekaran Jayakumar, Hsing-Ni Lee, Guan-Yi Lin, Chih-Hao Yang, Joen Rong Sheu |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Neurogenesis Endocrinology Diabetes and Metabolism Clinical Biochemistry Population lcsh:Medicine Histone deacetylase 6 Adult neurogenesis Brain Ischemia Mice 03 medical and health sciences 0302 clinical medicine In vivo Retroviral labeling Animals Medicine Pharmacology (medical) education Molecular Biology Stroke Environmental enrichment education.field_of_study Ischemic stroke business.industry Research Rehabilitation therapy lcsh:R Biochemistry (medical) Recovery of Function Cell Biology General Medicine HDAC6 Functional recovery medicine.disease Mice Inbred C57BL 030104 developmental biology 030220 oncology & carcinogenesis Female business Neuroscience |
| Zdroj: | Journal of Biomedical Science, Vol 26, Iss 1, Pp 1-17 (2019) Journal of Biomedical Science |
| ISSN: | 1423-0127 |
| DOI: | 10.1186/s12929-019-0521-1 |
| Popis: | Background Promoting post-stroke neurogenesis has long been proposed to be a therapeutic strategy for the enhancement of functional recovery after cerebral ischemic stroke. Despite numerous approaches have been widely reported the proliferation or differentiation of the neurogenic population therapeutic strategies by targeting adult neurogenesis not yet to be successfully clarified in clinical settings. Here, we hypothesized that alterations in microenvironment of the ischemic brain might impede the functional maturation of adult newly generated neurons that limits functional recovery after stroke. Methods The in vivo retroviral based labeling model was applied to directly birth-date and trace the maturation process of adult newly generating neurons after hypoxic challenge. A rehabilitation therapy procedure was adopted through the combination of task-specific motor rehabilitating training with environmental enrichment to promote functional recovery after stroke. In addition, a pharmacological or genetic suppression of HDAC6 was performed to evaluate the functional significance of HDAC6 in the pathology of ischemic stroke induced deficits. Results Serial morphological analyses at multiple stages along the maturation process showed significant retardation of the dendritic maturation on the newly generated neurons after stroke. Subsequent biochemical analyses revealed an aberrant nuclear translocation of HDAC6 that leads to the hyper-acetylation of α-tubulin (an indication of over-stabilized microtubules) after hypoxic challenge was observed at different time points after stroke. Furthermore, the mimicry experiments with either pharmacological or genetic suppression of HDAC6, phenocopied the stroke induced retardation in dendritic maturation of newly generating neurons in vivo. More importantly, we provide direct evidence showing the proper function of HDAC6 is required for rehabilitation therapy induced therapeutic benefits after stroke. Conclusion Together, our current study unravels that dysfunction of HDAC6 contributes to stroke induced deficits in neurogenesis and provides an innovative therapeutic strategy that targets HDAC6 for promoting functional recovery toward the patients with stroke in clinic. |
| Databáze: | OpenAIRE |
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