A Neuroprotective Role of Protein Kinase D in Huntington ́s Disease

Trabajo presentado en el VIII International Congress on Research and Innovation in Neurodegenerative Diseases (CIIIEN), celebrado en Madrid (España) del 21 al 22 de septiembre de 2021.Huntington’s Disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and psychiatric symptoms. The cause is a cytosine-adenine-guanine (CAG) repeat expansion within the coding region of the huntingtin (Htt) gene that generates aberrant proteins containing extended polyglutamine (polyQ) stretches affecting particularly the striatum and cerebral cortex. One of the underlying mechanisms proposed in HD neurotoxicity has been an initial overactivity of glutamate neurotransmission triggering excitotoxicity. In our lab, we have demonstrated that Protein Kinase D1 (PKD1) activity is neuroprotective, as it decreases excitotoxic neuronal death, reactive oxygen species accumulation and oxidative stress damage (Pose-Utrilla J. & Garc a-Guerra L. et al. Nat Comm 2017). Therefore, we wondered whether PKD1 activity could be disrupted in HD, compromising a hypothetical neuroprotective effect on inhibitory striatal medium spiny neurons (MSNs). Herein, we have examined brain necropsies from HD patients and cerebral samples from R6/1 HD mouse model and found a highly significant specific downregulation of PKD protein in striatal and cortical neurons. This decrease in PKD levels is probably due to transcriptional mechanisms. Importantly, pharmacological inhibition of PKD in cultured mouse striatal MSNs, enhances their vulnersability to excitotoxic insults. In addition, have also demonstrated that primary striatal MSNs transduced with lentivirus for the expression of a constitutively active PKD1 mutant (PKD1ca) are protected against excitotoxicity. Furthermore, PKD1ca is also able to hamper cell death caused by polyQ nuclear aggregates in a mouse neuroblastoma cell model of HD. Altogether, these results point to a possible novel contribution of this kinase to HD pathogenesis and open future therapeutic opportunities for this pathology