Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington's disease
<p>Abstract</p> <p>Background</p> <p>Huntington's disease (HD) is an inherited neurogenerative disease caused by an abnormal expansion of glutamine repeats in the huntingtin protein. There is currently no treatment to prevent the neurodegeneration caused by this de...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2009-10-01
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| Series: | Molecular Brain |
| Online Access: | http://www.molecularbrain.com/content/2/1/33 |
| _version_ | 1811284858308132864 |
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| author | Pineda Jose R Pardo Raúl Zala Diana Yu Hua Humbert Sandrine Saudou Frédéric |
| author_facet | Pineda Jose R Pardo Raúl Zala Diana Yu Hua Humbert Sandrine Saudou Frédéric |
| author_sort | Pineda Jose R |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Huntington's disease (HD) is an inherited neurogenerative disease caused by an abnormal expansion of glutamine repeats in the huntingtin protein. There is currently no treatment to prevent the neurodegeneration caused by this devastating disorder. Huntingtin has been shown to be a positive regulator of vesicular transport, particularly for neurotrophins such as brain-derived neurotrophic factor (BDNF). This function is lost in patients with HD, resulting in a decrease in neurotrophic support and subsequent neuronal death. One promising line of treatment is therefore the restoration of huntingtin function in BDNF transport.</p> <p>Results</p> <p>The phosphorylation of huntingtin at serine 421 (S421) restores its function in axonal transport. We therefore investigated whether inhibition of calcineurin, the <it>bona fide </it>huntingtin S421 phosphatase, restored the transport defects observed in HD. We found that pharmacological inhibition of calcineurin by FK506 led to sustained phosphorylation of mutant huntingtin at S421. FK506 restored BDNF transport in two complementary models: rat primary neuronal cultures expressing mutant huntingtin and mouse cortical neurons from <it>Hdh</it><sup>Q111/Q111 </sup>HD knock-in mice. This effect was the result of specific calcineurin inhibition, as calcineurin silencing restored both anterograde and retrograde transport in neurons from <it>Hdh</it><sup>Q111/Q111 </sup>mice. We also observed a specific increase in calcineurin activity in the brain of <it>Hdh</it><sup>Q111/Q111 </sup>mice potentially accounting for the selective loss of huntingtin phosphorylation and contributing to neuronal cell death in HD.</p> <p>Conclusion</p> <p>Our results validate calcineurin as a target for the treatment of HD and provide the first demonstration of the restoration of huntingtin function by an FDA-approved compound.</p> |
| first_indexed | 2024-04-13T02:35:53Z |
| format | Article |
| id | doaj.art-9bf3d31bf60249f9849bae539253819d |
| institution | Directory Open Access Journal |
| issn | 1756-6606 |
| language | English |
| last_indexed | 2024-04-13T02:35:53Z |
| publishDate | 2009-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Brain |
| spelling | doaj.art-9bf3d31bf60249f9849bae539253819d2022-12-22T03:06:22ZengBMCMolecular Brain1756-66062009-10-01213310.1186/1756-6606-2-33Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington's diseasePineda Jose RPardo RaúlZala DianaYu HuaHumbert SandrineSaudou Frédéric<p>Abstract</p> <p>Background</p> <p>Huntington's disease (HD) is an inherited neurogenerative disease caused by an abnormal expansion of glutamine repeats in the huntingtin protein. There is currently no treatment to prevent the neurodegeneration caused by this devastating disorder. Huntingtin has been shown to be a positive regulator of vesicular transport, particularly for neurotrophins such as brain-derived neurotrophic factor (BDNF). This function is lost in patients with HD, resulting in a decrease in neurotrophic support and subsequent neuronal death. One promising line of treatment is therefore the restoration of huntingtin function in BDNF transport.</p> <p>Results</p> <p>The phosphorylation of huntingtin at serine 421 (S421) restores its function in axonal transport. We therefore investigated whether inhibition of calcineurin, the <it>bona fide </it>huntingtin S421 phosphatase, restored the transport defects observed in HD. We found that pharmacological inhibition of calcineurin by FK506 led to sustained phosphorylation of mutant huntingtin at S421. FK506 restored BDNF transport in two complementary models: rat primary neuronal cultures expressing mutant huntingtin and mouse cortical neurons from <it>Hdh</it><sup>Q111/Q111 </sup>HD knock-in mice. This effect was the result of specific calcineurin inhibition, as calcineurin silencing restored both anterograde and retrograde transport in neurons from <it>Hdh</it><sup>Q111/Q111 </sup>mice. We also observed a specific increase in calcineurin activity in the brain of <it>Hdh</it><sup>Q111/Q111 </sup>mice potentially accounting for the selective loss of huntingtin phosphorylation and contributing to neuronal cell death in HD.</p> <p>Conclusion</p> <p>Our results validate calcineurin as a target for the treatment of HD and provide the first demonstration of the restoration of huntingtin function by an FDA-approved compound.</p>http://www.molecularbrain.com/content/2/1/33 |
| spellingShingle | Pineda Jose R Pardo Raúl Zala Diana Yu Hua Humbert Sandrine Saudou Frédéric Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington's disease Molecular Brain |
| title | Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington's disease |
| title_full | Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington's disease |
| title_fullStr | Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington's disease |
| title_full_unstemmed | Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington's disease |
| title_short | Genetic and pharmacological inhibition of calcineurin corrects the BDNF transport defect in Huntington's disease |
| title_sort | genetic and pharmacological inhibition of calcineurin corrects the bdnf transport defect in huntington s disease |
| url | http://www.molecularbrain.com/content/2/1/33 |
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