Huntington’s disease (HD) is characterised by motor disturbances associated to dysfunction and degeneration of the medium spiny neurons within the striatum.^1,2The molecular mechanisms underlying striatal vulnerability are still unknown, but growing evidences suggest that mitochondrial dysfunction occurs during the pathogenesis of the disease.³We previously described that deregulation of cyclin-dependent kinase 5 (Cdk5) activity induced by mutant huntingtin increases the susceptibility of striatal neurons to dopamine via D1 receptor activation.⁴Interestingly, Cdk5 has been shown to act as a mitochondrial regulator during neuronal apoptosis.⁵

Here, we investigated whether this aberrant Cdk5 signalling contributes to the striatal neurodegeneration by altering mitochondrial dynamics processes. We first observed that striatal cells expressing mutant huntingtin (mHtt) present increased mitochondrial fragmentation that worsens after dopaminergic stimuli. These mitochondrial defects can be widely rescued by Cdk5 inhibition with roscovitine or Cdk5 knockdown with siRNA transfection. Furthermore we found that mHtt deregulates the levels and the subcellular distribution of fission/fusion proteins while activation of D1 receptors promotes an increase in the levels of the fission protein Drp1 and its translocation to the mitochondria. We demonstrated that mHtt-induced Cdk5 activation is involved in the deregulation of the Drp1 GTPase activity since its inhibition prevents the aberrant activation of this fission protein.

Altogether, our findings support the hypothesis that Cdk5 plays a crucial role in mitochondrial defects involved in the striatal neurodegeneration in HD.

This study was supported by Ministerio de Innovación y Ciencia SAF2012–39142, CHDI Ministerio deSanidad y Consumo (CIBERNED CB06/05/0054), Fundación Ramón Areces.

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