Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment

Jun Wu, Hsin Pei Shih, Vladimir Vigont, Lori Hrdlicka, Len Diggins, Carol Singh, Matt Mahoney, Richard Chesworth, Gideon Shapiro, Olga Zimina, Xuesong Chen, Qingqing Wu, Lyubov Glushankova, Michael Ahlijanian, Gerhard Koenig, Galina N. Mozhayeva, Elena Kaznacheyeva, Ilya Bezprozvanny

Research output: Contribution to journalArticle

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Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion within Huntingtin (Htt) protein. In the phenotypic screen we identified a class of quinazoline-derived compounds that delayed a progression of a motor phenotype in transgenic Drosophila HD flies. We found that the store-operated calcium (Ca2+) entry (SOC) pathway activity is enhanced in neuronal cells expressing mutant Htt and that the identified compounds inhibit SOC pathway in HD neurons. The same compounds exerted neuroprotective effects in glutamate-toxicity assays with YAC128 medium spiny neurons primary cultures. We demonstrated a key role of TRPC1 channels in supporting SOC pathway in HD neurons. We concluded that the TRPC1-mediated neuronal SOC pathway constitutes a novel target for HD treatment and that the identified compounds represent a novel class of therapeutic agents for treatment of HD and possibly other neurodegenerative disorders.

Original languageEnglish (US)
Pages (from-to)777-793
Number of pages17
JournalChemistry and Biology
Volume18
Issue number6
DOIs
StatePublished - Jun 24 2011

Fingerprint

Huntington Disease
Calcium
Neurons
Neurodegenerative Diseases
Therapeutics
Quinazolines
Neuroprotective Agents
Diptera
Drosophila
Toxicity
Glutamic Acid
Assays
Cells
Phenotype
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Molecular Biology
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

Cite this

Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment. / Wu, Jun; Shih, Hsin Pei; Vigont, Vladimir; Hrdlicka, Lori; Diggins, Len; Singh, Carol; Mahoney, Matt; Chesworth, Richard; Shapiro, Gideon; Zimina, Olga; Chen, Xuesong; Wu, Qingqing; Glushankova, Lyubov; Ahlijanian, Michael; Koenig, Gerhard; Mozhayeva, Galina N.; Kaznacheyeva, Elena; Bezprozvanny, Ilya.

In: Chemistry and Biology, Vol. 18, No. 6, 24.06.2011, p. 777-793.

Research output: Contribution to journalArticle

Wu, J, Shih, HP, Vigont, V, Hrdlicka, L, Diggins, L, Singh, C, Mahoney, M, Chesworth, R, Shapiro, G, Zimina, O, Chen, X, Wu, Q, Glushankova, L, Ahlijanian, M, Koenig, G, Mozhayeva, GN, Kaznacheyeva, E & Bezprozvanny, I 2011, 'Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment', Chemistry and Biology, vol. 18, no. 6, pp. 777-793. https://doi.org/10.1016/j.chembiol.2011.04.012
Wu, Jun ; Shih, Hsin Pei ; Vigont, Vladimir ; Hrdlicka, Lori ; Diggins, Len ; Singh, Carol ; Mahoney, Matt ; Chesworth, Richard ; Shapiro, Gideon ; Zimina, Olga ; Chen, Xuesong ; Wu, Qingqing ; Glushankova, Lyubov ; Ahlijanian, Michael ; Koenig, Gerhard ; Mozhayeva, Galina N. ; Kaznacheyeva, Elena ; Bezprozvanny, Ilya. / Neuronal store-operated calcium entry pathway as a novel therapeutic target for Huntington's disease treatment. In: Chemistry and Biology. 2011 ; Vol. 18, No. 6. pp. 777-793.
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