Dopaminergic and Glutamatergic Signaling Crosstalk in Huntington's Disease Neurodegeneration: The Role of p25/Cyclin-Dependent Kinase 5

Abstract

Altered glutamatergic and dopaminergic signaling has been proposed as contributing to the specific striatal cell death observed in Huntington's disease (HD). However, the precise mechanisms by which mutant huntingtin sensitize striatal cells to dopamine and glutamate inputs remain unclear. Here, we demonstrate in knock-in HD striatal cells that mutant huntingtin enhances dopaminemediated striatal cell death via dopamine D 1 receptors. Moreover, we show that NMDA receptors specifically potentiate the vulnerability of mutant huntingtin striatal cells to dopamine toxicity as pretreatment with NMDA increased D 1 R-induced cell death in mutant but not wild-type cells. As potential underlying mechanism of increased striatal vulnerability, we identified aberrant cyclin-dependent kinase 5 (Cdk5) activation. We demonstrate that enhanced Cdk5 phosphorylation and increased calpain-mediated conversion of the Cdk5 activator p35 into p25 may account for the deregulation of Cdk5 associated to dopamine and glutamate receptor activation in knock-in HD striatal cells. Moreover, supporting a detrimental role of Cdk5 in striatal cell death, neuronal loss can be widely prevented by roscovitine, a potent Cdk5 inhibitor. Significantly, reduced Cdk5 expression together with enhanced Cdk5 phosphorylation and p25 accumulation also occurs in the striatum of mutant Hdh Q111 mice and HD human brain suggesting the relevance of deregulated Cdk5 pathway in HD pathology. These findings provide new insights into the molecular mechanisms underlying the selective vulnerability of striatal cells in HD and identify p25/Cdk5 as an important mediator of dopamine and glutamate neurotoxicity associated to HD.

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease

“…STHdh Q111/Q111 cells express exon 1 of the mutant human huntingtin gene containing 111 CAG repeats knocked into the mouse huntingtin locus (Trettel et al., 2000). STHdh Q7/Q7 and STHdh Q111/Q111 cells endogenously express CB 1 and dopamine D 2 receptor (Paoletti et al, 2008;Laprairie et al, 2014). Cells were maintained at 33°C, 5% CO 2 in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 10 4 IU ml 21 penicillin/streptomycin, and 400 mg ml 21 geneticin.…”

Flavopiridol induces phosphorylation of AKT in a human glioblastoma cell line, in contrast to siRNA-mediated silencing of Cdk9: Implications for drug design and development

“…5,[8][9][10][11][12] Preclinical studies are currently ongoing to apply protein kinase inhibitors for the treatment of various neurological disorders. [65][66][67][68] However, flavopiridol and seliciclib provided modest outcomes in patients with cancer. [8][9][10][11][12]56 Meanwhile, new generations of protein kinases inhibitors were produced and used in early stages clinical trials for the treatment of cancer.…”

Cdk5 activity in the brain – multiple paths of regulation

“…Cdk5 inhibition confers neuroprotection in in vivo models of ischemia and stroke, underscoring its crucial role in disease progression (Menn et al, 2010). In the case of HD, Cdk5 deregulation is linked to striatal neuronal death (Paoletti et al, 2008).…”