Biology Reference
In-Depth Information
required to induce the cell death associated with abnormal phosphorylation of tau in AD
(Yoshizaki, et al. 2004). The involvement of phosphorylation of tau in apoptosis resembling
AD was demonstrated using a model comprising P19 cells stably expressing human tau441
(tau/P19 cells) (Tsukane & Yamauchi, 2006). CaMKII is involved in the apoptosis of P19
cells expressing tau during neural differentiation induced by retinoic acid treatment.If
CaMKII had been abnormally activated, due to a breakdown of the normal regulatory
mechanisms, it would be responsible for the phosphorylation of tau in the AD brain.
6-2. Angelman's mental retardation syndrome
Angelman's mental retardation syndrome is a disorder of human cognition characterized
by severe mental retardation and epilepsy. The
Ube3a
gene is identified as the genetic locus
for Angelman's syndrome (Albrecht, et al. 1997). The
Ube3a
gene encodes for an E6-AP
ubiquitin ligase, an enzyme involved in protein degradation through the ubiquitin-associated
proteosome-mediated pathway. The behavioral phenotype of mice with a maternal deficiency
in
Ube3a
resembles Angelman's syndrome, manifesting motor dysfunction, inducible
seizures, and context-dependent association learning deficits (Weeber, et al. 2003). LTP is
also severely impaired in the mice. Animal models of Angelman's syndrome exhibit a
significant increase in phosphorylation at Thr268 and Thr305, with no corresponding change
in the total level of CaMKII. Phosphorylation at Thr305 reduces CaMKII activity and its
affinity for the PSD. These observations confirm that the phosphorylation at Thr305 is
involved in the inhibition of synaptic responses. Thus, misregulation of CaMKII function
may cause the neurological symptoms in Angelman's syndrome. The misregulation is
probably caused by the decreased protein phosphatase PP1/PP2 activity (Weeber, et al. 2003).
6-3. Parkinson's disease, schizophrenia and pain
Parkinson's disease (PD) involves the degeneration of dopamine-containing nigrostriatal
neurons leading to the motor symptoms observed in this disorder. It is demonstrated that
NMDA receptor NR1 subunit and PSD-95 protein levels are selectively reduced in the PSD
of dopamine -denervated striata in experimental Parkinsonism. These effects are accompanied
by an increase in striatal levels of α CaMKII autophosphorylation. Abnormal α CaMKII
autophosphorylation plays a causal role in the alterations of striatal plasticity and motor
behavior that follow dopamine denervation. Normalization of CaMKII activity may be an
important underlying mechanism of the therapeutic action of L-DOPA in PD (Picconi et al.,
2004).
In searching for genes dysregulated in neuronal disease, it has been reported that the
mRNA level of CaMKII is significantly elevated in postmortem frontal cerebral cortex tissues
from patients who had died with schizophrenia, bipolar disorder, or severe, suggesting that
altered expression of CaMKII in the cerebral cortex contributes to these diseases (Novak et al.
2006).
Relationship between CaMKII and pain has also been investigated. In morphine-treated
mice, the levels of α CaMKII mRNA and protein were robustly increased and the abundance
