HDAC6 dysfunction contributes to impaired maturation of adult neurogenesis in vivo: vital role on functional recovery after ischemic stroke

Joen-Rong Sheu, Cheng-Ying Hsieh, Thanasekaran Jayakumar, Guan-Yi Lin, Hsing-Ni Lee, Shin-Wei Huang, Chih-Hao Yang

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number27
JournalJournal of Biomedical Science
Volume26
Issue number1
DOIs
Publication statusPublished - Apr 18 2019

Fingerprint

Neurogenesis
Neurons
Stroke
Recovery
Patient rehabilitation
Acetylation
Pathology
Tubulin
Genetic Suppression
Labeling
Brain
Therapeutics
Rehabilitation
Pharmacology
Experiments
Microtubules
Parturition

Keywords

  • Adult neurogenesis
  • Histone deacetylase 6
  • Ischemic stroke
  • Rehabilitation therapy
  • Retroviral labeling

ASJC Scopus subject areas

  • Biochemistry, medical
  • Pharmacology (medical)
  • Molecular Biology
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology

Cite this

HDAC6 dysfunction contributes to impaired maturation of adult neurogenesis in vivo : vital role on functional recovery after ischemic stroke. / Sheu, Joen-Rong; Hsieh, Cheng-Ying; Jayakumar, Thanasekaran; Lin, Guan-Yi; Lee, Hsing-Ni; Huang, Shin-Wei; Yang, Chih-Hao.

In: Journal of Biomedical Science, Vol. 26, No. 1, 27, 18.04.2019.

Research output: Contribution to journalArticle

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AB - 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.

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