Expanded-polyglutamine Huntingtin protein suppresses the secretion and production of a chemokine (CCL5/RANTES) by astrocytes

Szu Yi Chou, Ju Yun Weng, Hsing Lin Lai, Fang Liao, Synthia H. Sun, Pang Hsien Tu, Dennis W. Dickson, Yijuang Chern

Research output: Contribution to journalArticlepeer-review

78 Citations (Scopus)

Abstract

Huntington's disease (HD) is a hereditary neurological disease caused by expended CAG repeats in the HD gene, which codes for a protein called Huntingtin (Htt). The resultant mutant Huntingtin (mHtt) forms aggregates in neurons and causes neuronal dysfunction. In astrocytes, the largest population of brain cells, mHtt also exists. We report herein that astrocyte-conditioned medium (ACM) collected from astrocytes of R6/2 mice (a mouse model of HD) caused primary cortical neurons to grow less-mature neurites, migrate more slowly, and exhibit lower calcium influx after depolarization than those maintained in wild-type (WT) ACM. Using a cytokine antibody array and ELISA assays, we demonstrated that the amount of a chemokine [chemokine (C-C motif) ligand 5 (CCL5)/regulated on activation normal T cell expressed and secreted (RANTES)] released by R6/2 astrocytes was much less than that by WT astrocytes. When cortical neurons were treated with the indicated ACM, supplementation with recombinant CCL5/RANTES ameliorated the neuronal deficiency caused by HD-ACM, whereas removing CCL5/RANTES from WT-ACM using an anti-CCL5/RANTES antibody mimicked the effects evoked by HD-ACM. Quantitative PCR and promoter analyses demonstrated that mHtt hindered the activation of the CCL5/RANTES promoter by reducing the availability of nuclear factor κB-p65 and, hence, reduced the transcript level of CCL5/RANTES. Moreover, ELISA assays and immunocytochemical staining revealed that mHtt retained the residual CCL5/RANTES inside R6/2 astrocytes. In line with the above findings, elevated cytosolic CCL5/RANTES levels were also observed in the brains of two mouse models ofHD[R6/2 and Hdh(CAG)150] and human HD patients. These findings suggest that mHtt hinders one major trophic function of astrocytes which might contribute to the neuronal dysfunction of HD.

Original languageEnglish
Pages (from-to)3277-3290
Number of pages14
JournalJournal of Neuroscience
Volume28
Issue number13
DOIs
Publication statusPublished - Mar 26 2008
Externally publishedYes

Keywords

  • Astrocyte
  • Huntington
  • Neuron
  • Release
  • Transcription
  • Trophic

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Expanded-polyglutamine Huntingtin protein suppresses the secretion and production of a chemokine (CCL5/RANTES) by astrocytes'. Together they form a unique fingerprint.

Cite this