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HDAC4: a key factor underlying brain developmental alterations in CDKL5 disorder.

Stefania Trazzi1, Claudia Fuchs1, Rocchina Viggiano1

  • 1Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy.

Human Molecular Genetics
|July 29, 2016
PubMed
Summary

Cyclin-dependent kinase-like 5 (CDKL5) mutations cause neurodevelopmental disorders. CDKL5 phosphorylates histone deacetylase 4 (HDAC4), regulating its nuclear entry and neuronal gene expression. Inhibiting HDAC4 rescues neurological deficits in a CDKL5 disorder mouse model.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Cyclin-dependent kinase-like 5 (CDKL5) mutations cause severe neurodevelopmental disorders.
  • Understanding CDKL5's phosphorylation targets is crucial for developing therapeutic strategies.
  • The precise molecular mechanisms underlying CDKL5 disorder remain largely unknown.

Purpose of the Study:

  • To identify direct phosphorylation targets of CDKL5.
  • To elucidate the role of CDKL5-mediated phosphorylation in neuronal function and development.
  • To investigate the therapeutic potential of targeting CDKL5-interacting proteins in CDKL5 disorder.

Main Methods:

  • Western blotting and immunoprecipitation to identify CDKL5 phosphorylation targets.
  • Immunofluorescence and subcellular fractionation to assess HDAC4 localization.
  • Analysis of gene expression and histone acetylation in neural precursor cells.
  • Behavioral testing and histological analysis in a Cdkl5 knockout mouse model.

Main Results:

  • Histone deacetylase 4 (HDAC4) is identified as a direct CDKL5 phosphorylation target.
  • CDKL5-dependent phosphorylation promotes cytoplasmic retention of HDAC4.
  • In Cdkl5 knockout mice, hypophosphorylated HDAC4 accumulates in the nucleus, reducing histone acetylation and impairing neuronal precursor cell development and memory.
  • Pharmacological inhibition of HDAC4 with LMK235 normalized neuronal development and cognitive function in Cdkl5 knockout mice.

Conclusions:

  • HDAC4 is a key mediator of neurodevelopmental alterations in CDKL5 disorder.
  • CDKL5 regulates neuronal gene expression through phosphorylation-dependent control of HDAC4 localization.
  • Targeting HDAC4 offers a promising therapeutic avenue for CDKL5-related neurodevelopmental pathologies.