Biphasic developmental changes in Ca2+/calmodulin-dependent proteins in R6/2 Huntington??s disease mice

Widespread disturbances in calcium-dependent proteins are reported both in humans with advanced Huntington's disease (HD) and in symptomatic HD transgenic mice. Using a HD mouse model transgenic for exon 1 of the abnormal gene (e.g. the Bates R6/2 mouse), we found increased expression of calmodulin kinase IV and neuronal nitric oxide synthase (NOS) in 3-week-old presymptomatic HD mice striatum and cortex. Conversely, reduced expression was found at 6 weeks (early symptom onset) and 11 weeks (advanced disease) of age. The changes in protein expression may have a broad impact on the HD striatum. Calmodulin kinase IV directly regulates the activation of the transcription factors CREB (cyclic AMP response element binding protein) and CREM (cyclic AMP response element modulator) and, as well, modulates the activity of neuronal NOS. In homeostasis, nitric oxide is involved in long-term potentiation, neurotransmission, endocrine regulation and cerebral blood flow regulation, among others, while under pathological conditions nitric oxide combines with superoxide to produce the potent neurotoxin peroxynitrite. The current findings suggest that mutant HD protein may alter these processes by disturbing the regulation of calmodulin kinase IV and neuronal NOS expression across the lifespan of the HD mouse.