Abstract
BackgroundHuntington'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.ResultsThe phosphorylation of huntingtin at serine 421 (S421) restores its function in axonal transport. We therefore investigated whether inhibition of calcineurin, the bona fide 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 HdhQ111/Q111 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 HdhQ111/Q111 mice. We also observed a specific increase in calcineurin activity in the brain of HdhQ111/Q111 mice potentially accounting for the selective loss of huntingtin phosphorylation and contributing to neuronal cell death in HD.ConclusionOur 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.
Highlights
Huntington's disease (HD) is an inherited neurogenerative disease caused by an abnormal expansion of glutamine repeats in the huntingtin protein
FK506 increases huntingtin phosphorylation at serine 421 (S421) in primary cortical neurons from HdhQ111/Q111 mice Previous studies have demonstrated that calcineurin dephosphorylates the S421 residue of huntingtin in rat cultures in vitro and that calcineurin inhibition results in an increase in huntingtin phosphorylation in transfected cells [15]
FK506 inhibits calcineurin activity in cortical neurons from HdhQ111/Q111 mice We investigated whether FK506 treatment, which induced a significant increase in huntingtin phosphorylation and corrected the axonal transport defect due to mutant huntingtin, led to calcineurin inhibition
Summary
Huntington's disease (HD) is an inherited neurogenerative disease caused by an abnormal expansion of glutamine repeats in the huntingtin protein. An abnormal polyglutamine (polyQ) expansion in the Nterminal part of the huntingtin protein causes Huntington's disease (HD), a fatal neurodegenerative disorder characterized by the dysfunction and death of striatal and cortical neurons in the brain [1]. Several groups have demonstrated changes in the microtubule (MT)-dependent transport of vesicles, such as those containing brain-derived neurotrophic factor (BDNF), in diseased neurons [3,4,5,6,7] This trafficking defect is an early pathogenic event and is linked to the association of huntingtin with components of the molecular motor machinery [3,8,9,10,11,12,13] and its function as a direct regulator of MT-dependent transport in different cell type including neurons [3,10,12]
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