The Proteasome in Neurodegeneration
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Interestingly, during ischemia the hippocampal subfield CA1 showed the strongest reduction in the catalytic activity of the proteasome [ 71 ], similar to findings in our mouse model of status epilepticus , suggesting that some similarities may exist between different conditions. We do not know why the hippocampal subfield CA1 is more prone to a reduction in proteasome activity after seizures and why this downregulation is not accompanied by a bigger increase in polyubiquitinated proteins after status epilepticus when compared to the other hippocampal subfields.
Differences in glutamate receptor recruitment during status epilepticus e. NMDA subtype vs. Why does UPS impairment protect against seizure-induced cell death? The protection is presumably a result of an accumulation of proteins that would otherwise be degraded. However, we do not know their identity. Other proteins such as heat shock proteins [ 74 ] or synaptic proteins may also be involved. Another option may be that accumulated proteins interrupt signalling pathways that would normally be able to progress through to kill neurons or, alternatively, the inhibition of the ATP-consuming UPS may help protect against excessive depletion of energy reserves during seizures.
Emerging evidence suggests that the UPS controls neurotransmission by regulating crucial processes such as synaptic plasticity, spinogenesis and levels of functional neurotransmitter receptors [ 17 ]. We have not observed any changes in seizure severity during status epilepticus after epoxomicin treatment.
However, a potential impact of the proteasome on seizure generation or seizure severity might be more important under chronic conditions.
Epileptic mice in our study showed increased polyubiquitination levels in the hippocampus suggesting a chronic impairment of the UPS which may contribute to hyperexcitability. In line with this, recent data has shown a more severe epileptic phenotype in rats treated with the proteasome inhibitor MG [ 75 ], which, in contrast to epoxomicin, also inhibits calpain activity [ 76 ].
Indeed, inhibition of the UPS has been reported to elicit neurodegeneration directly [ 8 , 45 ]. Therefore, it is unlikely proteasome inhibitors will be used as neuroprotective or anti-epileptic drugs. Our data show that prolonged seizures lead to an impairment of the UPS which is most prominent in brain areas resistant to seizure-induced cell death suggesting proteasome inhibition as an endogenous protective mechanism.
The main experiments used the intra-amygdala KA-induced status epilepticus [ 36 ]. Then, mice were placed in a stereotaxic frame and following a midline scalp incision, three partial craniotomies were performed. Non-seizure control animals received the same volume of intra-amygdala vehicle. Cortical EEG recordings were analyzed off-line using manual assessment as described [ 77 ]. Changes in seizure-induced behaviour were scored according to a modified Racine Scale as reported previously [ 78 ].
Score 1, immobility and freezing; Score 2, forelimb and or tail extension, rigid posture; 3, repetitive movements, head bobbing; Score 4, rearing and falling; Score 5, continuous rearing and falling; Score 6, severe tonic—clonic seizures. Drugs were delivered via intracerebroventricular i. Fluorescence signals were normalized to the protein concentrations, which were determined by Bradford assay Thermo Fisher Scientific, Dublin, Ireland. Western blotting was performed as previously described [ 40 ]. Whole hippocampi or hippocampal subfields dentate gyrus DG , CA1 and CA3 were homogenized in lysis buffer and protein concentration was determined.
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Total mRNA was extracted as previously described using the Trizol protocol [ 40 ]. Counts were the average of two adjacent sections assessed by an observer blinded to treatment. Sections were rinsed and treated with PBS containing 0. Images were analyzed using ImageJ. DAB staining was performed as described before [ 77 ]. Chromogen reactions were performed with diaminobenzidine Sigma-Aldrich, Dublin, Ireland and 0. Primary cultures of hippocampal neurons were prepared from E Cells were then treated with 0.
Cells were stained with PI and Hoechst and a minimum of three pictures were taken per experiment 20 x lens blinded to treatment. Cell death was calculated as percentage of PI uptake in relation to Hoechst-positive cells. Samples were then processed for Western blotting as described before [ 77 ]. Cold Spring Harb Perspect Med. Pitkanen A, Lukasiuk K.
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Heat Shock Proteins and Proteasome Function in Neurodegeneration
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