Cdk5-mediated mitochondrial fission: A key player in dopaminergic toxicity in Huntington's disease

• Cdk5-mediated alterations in Drp1 function contribute to mitochondrial fission in HD.
• D1R activation aggravates mitochondrial defects in mutant huntingtin striatal cells.
• D1R induced mitochondrial fission in mutant huntingtin cells depends on Cdk5 activity.
• Deregulated Cdk5 function by D1R activation modifies Drp1 distribution and activity.
• Modulation of Cdk5 signaling may prevent or ameliorate striatal neurodegeneration in HD.

The molecular mechanisms underlying striatal vulnerability in Huntington's disease (HD) are still unknown. However, growing evidence suggest that mitochondrial dysfunction could play a major role. In searching for a potential link between striatal neurodegeneration and mitochondrial defects we focused on cyclin-dependent kinase 5 (Cdk5). Here, we demonstrate that increased mitochondrial fission in mutant huntingtin striatal cells can be a consequence of Cdk5-mediated alterations in Drp1 subcellular distribution and activity since pharmacological or genetic inhibition of Cdk5 normalizes Drp1 function ameliorating mitochondrial fragmentation. Interestingly, mitochondrial defects in mutant huntingtin striatal cells can be worsened by D1 receptor activation a process also mediated by Cdk5 as down-regulation of Cdk5 activity abrogates the increase in mitochondrial fission, the translocation of Drp1 to the mitochondria and the raise of Drp1 activity induced by dopaminergic stimulation. In sum, we have demonstrated a new role for Cdk5 in HD pathology by mediating dopaminergic neurotoxicity through modulation of Drp1-induced mitochondrial fragmentation, which underscores the relevance for pharmacologic interference of Cdk5 signaling to prevent or ameliorate striatal neurodegeneration in HD.