Reduced levels of proteasome products in a mouse striatal cell model of huntington's disease

Sayani Dasgupta, Michael A. Fishman, Hana Mahallati, Leandro M. Castro, Alexandre K. Tashima, Emer S. Ferro, Lloyd D. Fricker

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Huntington's disease is the result of a long polyglutamine tract in the gene encoding huntingtin protein, which in turn causes a large number of cellular changes and ultimately results in neurodegeneration of striatal neurons. Although many theories have been proposed, the precise mechanism by which the polyglutamine expansion causes cellular changes is not certain. Some evidence supports the hypothesis that the long polyglutamine tract inhibits the proteasome, a multiprotein complex involved in protein degradation. However, other studies report normal proteasome function in cells expressing long polyglutamine tracts. The controversy may be due to the methods used to examine proteasome activity in each of the previous studies. In the present study, we measured proteasome function by examining levels of endogenous peptides that are products of proteasome cleavage. Peptide levels were compared among mouse striatal cell lines expressing either 7 glutamines (STHdhQ7/Q7) or 111 glutamines in the huntingtin protein, either heterozygous (STHdhQ7/Q111) or homozygous (STHdhQ111/Q111). Both of the cell lines expressing huntingtin with 111 glutamines showed a large reduction in nearly all of the peptides detected in the cells, relative to levels of these peptides in cells homozygous for 7 glutamines. Treatment of STHdhQ7/Q7 cells with proteasome inhibitors epoxomicin or bortezomib also caused a large reduction in most of these peptides, suggesting that they are products of proteasome-mediated cleavage of cellular proteins. Taken together, these results support the hypothesis that proteasome function is impaired by the expression of huntingtin protein containing long polyglutamine tracts.

Original languageEnglish (US)
Article numbere0145333
JournalPLoS One
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2015

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Corpus Striatum
disease models
Huntington Disease
proteasome endopeptidase complex
Proteasome Endopeptidase Complex
Glutamine
mice
glutamine
peptides
Peptides
cells
Cells
Proteins
cell lines
Cell Line
Multiprotein Complexes
Proteasome Inhibitors
Gene encoding
multiprotein complexes
proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Dasgupta, S., Fishman, M. A., Mahallati, H., Castro, L. M., Tashima, A. K., Ferro, E. S., & Fricker, L. D. (2015). Reduced levels of proteasome products in a mouse striatal cell model of huntington's disease. PLoS One, 10(12), [e0145333]. https://doi.org/10.1371/journal.pone.0145333

Reduced levels of proteasome products in a mouse striatal cell model of huntington's disease. / Dasgupta, Sayani; Fishman, Michael A.; Mahallati, Hana; Castro, Leandro M.; Tashima, Alexandre K.; Ferro, Emer S.; Fricker, Lloyd D.

In: PLoS One, Vol. 10, No. 12, e0145333, 01.12.2015.

Research output: Contribution to journalArticle

Dasgupta, S, Fishman, MA, Mahallati, H, Castro, LM, Tashima, AK, Ferro, ES & Fricker, LD 2015, 'Reduced levels of proteasome products in a mouse striatal cell model of huntington's disease', PLoS One, vol. 10, no. 12, e0145333. https://doi.org/10.1371/journal.pone.0145333
Dasgupta S, Fishman MA, Mahallati H, Castro LM, Tashima AK, Ferro ES et al. Reduced levels of proteasome products in a mouse striatal cell model of huntington's disease. PLoS One. 2015 Dec 1;10(12). e0145333. https://doi.org/10.1371/journal.pone.0145333
Dasgupta, Sayani ; Fishman, Michael A. ; Mahallati, Hana ; Castro, Leandro M. ; Tashima, Alexandre K. ; Ferro, Emer S. ; Fricker, Lloyd D. / Reduced levels of proteasome products in a mouse striatal cell model of huntington's disease. In: PLoS One. 2015 ; Vol. 10, No. 12.
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