Journal Article

Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice

Silvia Gines, Ihn Sik Seong, Elisa Fossale, Elena Ivanova, Flavia Trettel, James F. Gusella, Vanessa C. Wheeler, Francesca Persichetti and Marcy E. MacDonald

in Human Molecular Genetics

Volume 12, issue 5, pages 497-508
Published in print March 2003 | ISSN: 0964-6906
Published online March 2003 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddg046
Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice

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Defects in gene transcription and mitochondrial function have been implicated in the dominant disease process that leads to the loss of striatal neurons in Huntington's disease (HD). Here we have used precise genetic HD mouse and striatal cell models to investigate the hypothesis that decreased cAMP responsive element (CRE)-mediated gene transcription may reflect impaired energy metabolism. We found that reduced CRE-signaling in HdhQ111 striatum, monitored by brain derived neurotrophic factor and phospho-CRE binding protein (CREB), predated inclusion formation. Furthermore, cAMP levels in HdhQ111 striatum declined from an early age (10 weeks), and cAMP was significantly decreased in HD postmortem brain and lymphoblastoid cells, attesting to a chronic deficit in man. Reduced CRE-signaling in cultured STHdhQ111 striatal cells was associated with cytosolic CREB binding protein that mirrored diminished cAMP synthesis. Moreover, mutant cells exhibited mitochondrial respiratory chain impairment, evidenced by decreased ATP and ATP/ADP ratio, impaired MTT conversion and heightened sensitivity to 3-nitropropionic acid. Thus, our findings strongly suggest that impaired ATP synthesis and diminished cAMP levels amplify the early HD disease cascade by decreasing CRE-regulated gene transcription and altering energy dependent processes essential to neuronal cell survival.

Journal Article.  6585 words.  Illustrated.

Subjects: Genetics and Genomics

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