Therapeutics for Polyglutamine Diseases Through Protein Degradation Pathway: Targeting the Nucleus

  • Atsushi IwataEmail author


Polyglutamine diseases are caused by cytosine-adenine-guanine (CAG) trinucleotide expansions that are translated to a polyglutamine (pQ) chain in specific genes. This pQ chains tend to destabilize the entire proteins making them aggregate. The aggregates are especially toxic in the nucleus for a variety of reasons. Thus, for treating pQ diseases, targeting the nuclear pQ aggregates for degradation seems to be a promising approach. The nuclear ubiquitin proteasome system is the only major protein degradation machinery in the nucleus since the autophagy lysosome system, one of the major cytoplasmic protein degradation machinery, cannot function in the nucleus. There are ubiquitin ligases that recognize and promote nuclear pQ degradation, thus activation of these ubiquitin ligases could be one of the therapeutic approaches. We found that one of the histone deacetylases (HDAC), HDAC3, regulates the nuclear ubiquitin proteasome system. Although we may be closer to finding a molecular therapeutic approach for pQ diseases, rigorous effort to study the basic pathomechanisms of pQ diseases are necessary in order to expand our knowledge and find better therapeutics for these devastating diseases.


Polyglutamine Aggregate Histone deacetylases Proteasome Huntington’s disease Cellular compartment 


Conflict of Interest

The author has nothing to declare for COI disclosure.


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Copyright information

© Springer Japan 2015

Authors and Affiliations

  1. 1.Department of Neurology, Graduate School of MedicineThe University of TokyoTokyoJapan
  2. 2.Japan Science and Technology AgencyPRESTOSaitamaJapan

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