Cdk5-Dependent Activation of Neuronal Inflammasomes in Parkinson's Disease.

BACKGROUND: Inflammasomes, which mediate the activation of caspase-1 and maturation of IL-1ß and IL-18, have been unambiguously verified to participate in many diseases, such as lung diseases, infectious diseases and Alzheimer's disease, but the relation between Parkinson's disease and inflammasomes is poorly understood. METHODS: The expression, maturation, and secretion of inflammasomes in neurons were measured. The activation of inflammasomes in the substantia nigra of the brain was tested in acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and an α-synuclein transgenic mouse model. The levels of IL-1ß and IL-18 in cerebrospinal fluid and serum samples of Parkinson's disease (PD) patients and control subjects were measured. The role of cyclin-dependent kinase 5 (Cdk5) in neuronal inflammasome activation was evaluated using the pharmacological Cdk5 inhibitor roscovitine or Cdk5-targeted deletion. RESULTS: Here, we observed the expression of core molecules of inflammasomes, including NALP3, ASC, caspase-1, and IL-1ß, in neuronal cells. The PD inducer rotenone could activate neuronal inflammasomes and promote the maturation and secretion of the cleaved IL-1ß and IL-18 in a dose- and time-dependent manner. We also detected the activation of inflammasomes in the substantia nigra of a PD mouse model and in cerebrospinal fluid of PD patients. Furthermore, Cdk5 is required for the activation of inflammasomes, and both inhibition and deletion of Cdk5 could efficiently block inflammasome activation in PD models. CONCLUSIONS: Together, our results indicated that Cdk5-dependent activation of neuronal inflammasomes was involved in the progression of PD.

Phosphorylation of Connexin 43 by Cdk5 Modulates Neuronal Migration During Embryonic Brain Development.

The gap junction protein, connexin 43 (Cx43), is only present and abundantly expressed in astrocytes but is absent in neurons in the mature brain tissues. However, both the expression and function of Cx43 in neurons during brain embryonic development remain largely unexplored. In the present study, we confirmed that Cx43 is expressed in the migrating neurons in the embryonic stage of the brain. Neuron-specific Cx43 conditional knockout (cKO) using Cre-loxP technique impairs neuronal migration and formation of laminar structure in cerebral cortex during brain embryonic development. The animal behavior tests demonstrated that, at the adult stage, neuronal Cx43 cKO mice exhibit normal learning and memory functions but increased anxiety-like behavior. We also found that during the embryonic development, the gradually decreased Cx43 expression in the cortex is closely correlated with the upregulation of cyclin-dependent kinase 5 (Cdk5) activity. Cdk5 directly phosphorylates Cx43 at Ser279 and Ser282, which, in consequence, inhibits the membrane targeting of Cx43 and promotes its proteasome-dependent degradation. In summary, our findings revealed that the embryonic expression of Cx43 in neurons regulates processes of neuronal migration and positioning in the developing brain by controlling astrocyte-neuron interactions during brain embryonic development, and Cdk5 directly phosphorylates Cx43, which regulates the membrane localization and degradation of Cx43 in neurons.

[Expressions of eNOS and cytochrome P450 in the testis of sexually mature SD rats and their significance].

OBJECTIVE: To explore the expressions of endothelial nitric oxide synthase (eNOS) and cytochrome P450 (aromatase) in the testis of sexually mature male SD rats and their significance. METHODS: Eighteen male SD rats, 6 five-week, 6 seven-week and 6 ten-week old, were selected for this study. Paraffin sections of the left testis were made and the expressions of eNOS and P450 observed by the immunohistochemical ABC method. RESULTS: Positive expressions of eNOS and P450 were found to be + + +, + and + + in the Leydig cells of the five-week, seven-week and ten-week old rats, respectively, and they were also observed in a few spermatocytes, though with no regularity. CONCLUSION: In the Leydig cells of sexually mature male SD rats, eNOS and P450 are differently expressed in different stages of sexual maturation, and they are correlated as well.