QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, December 3, 2008, 28(49):13285-13295; doi:10.1523/JNEUROSCI.4393-08.2008

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Tydlacka, S. Articles by Li, X.-J. Search for Related Content PubMed PubMed Citation Articles by Tydlacka, S. Articles by Li, X.-J.

 Previous Article  |  Next Article 

Neurobiology of Disease
Differential Activities of the Ubiquitin–Proteasome System in Neurons versus Glia May Account for the Preferential Accumulation of Misfolded Proteins in Neurons

Suzanne Tydlacka,^1,2 Chuan-En Wang,¹ Xuejun Wang,³ Shihua Li,¹ and Xiao-Jiang Li¹

¹Department of Human Genetics and ²Neuroscience Graduate Program, Emory University School of Medicine, Atlanta, Georgia 30322, and ³Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, South Dakota 57069

Correspondence should be addressed to either of the following: Dr. Shihua Li or Xiao-Jiang Li, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322. Email: sli{at}emory.edu; Email: xli2{at}emory.edu

A variety of neurological disorders and polyglutamine (polyQ) diseases are caused by misfolded proteins. The common feature of these diseases is late-onset cellular degeneration that selectively affects neurons in distinct brain regions. polyQ diseases, including Huntington's disease (HD), present a clear case of selective neurodegeneration caused by polyQ expansion-induced protein misfolding, which also leads to predominant inclusions in neuronal nuclei. It remains unclear how these ubiquitously expressed disease proteins selectively kill neurons. In HD, mutant huntingtin accumulates in both neurons and glia, but more neuronal cells display huntingtin aggregates. These aggregates colocalize with components of the ubiquitin-proteasome system (UPS), which plays a critical role in clearing misfolded proteins. Using fluorescent reporters that reflect cellular UPS activity, we found that UPS activity in cultured neurons and glia decreases in a time-dependent manner. Importantly, UPS activity is lower in neurons than in glia and also lower in the nucleus than the cytoplasm. By expressing the UPS reporters in glia and neurons in the mouse brain, we also observed an age-dependent decrease in UPS activity, which is more pronounced in neurons than glial cells. Although brain UPS activities were similar between wild-type and HD 150Q knock-in mice, inhibiting the UPS markedly increases the accumulation of mutant htt in cultured glial cells. These findings suggest that the lower neuronal UPS activity may account for the preferential accumulation of misfolded proteins in neurons, as well as their selective vulnerability.

Key words: ubiquitin; proteasome; huntingtin; polyglutamine; aggregates; degeneration

---

Received Sept. 14, 2008; revised Oct. 17, 2008; accepted Oct. 21, 2008.

Correspondence should be addressed to either of the following: Dr. Shihua Li or Xiao-Jiang Li, Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322. Email: sli{at}emory.edu; Email: xli2{at}emory.edu

This article has been cited by other articles:

				M.-C. Chiang, H.-M. Chen, H.-L. Lai, H.-W. Chen, S.-Y. Chou, C.-M. Chen, F.-J. Tsai, and Y. Chern The A2A adenosine receptor rescues the urea cycle deficiency of Huntington's disease by enhancing the activity of the ubiquitin-proteasome system Hum. Mol. Genet., August 15, 2009; 18(16): 2929 - 2942. [Abstract] [Full Text] [PDF]

				H. L. Montie, M. S. Cho, L. Holder, Y. Liu, A. S. Tsvetkov, S. Finkbeiner, and D. E. Merry Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy Hum. Mol. Genet., June 1, 2009; 18(11): 1937 - 1950. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help