Table 1.
Mechanisms of action of IP and/or SP inhibitors and their reference to IP and SP status in specific CNS disorders.
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Mechanism of action of proteasome inhibitors tested in CNS disorders PR-957 (also known as ONX 0914): irreversible β5i -selective epoxyketone inhibitor (98, 99) PR-825: irreversible β5-specific inhibitor (99, 100) PeK (Peptidyl epoxyketone): β1i-selective epoxyketone inhibitor (101) PS-341 (Bortezomib): reversible dipeptide boronate inhibitor of SP and IP with high affinity for subunits (β5, β5i and β1i) with chymotrypsin-like activity (101, 102) PS-519 (Lactacystin-like compound): irreversible inhibitor of both SP and IP with higher affinity for chymotrypsin- and trypsin-like activity (β2, β5, β1i, β2i, β5i) (54, 57, 103) Epoxomycin: irreversible and selective inhibitor of both SP and IP with high affinity for chymotrypsin-like and trypsin-like activity (β2, β5, β1i, β2i, β5i) (54) MG-132: nonspecific inhibitor of all β subunits of the 20S core particles within both SP and IP (101, 104) Rapamycin: mTOR inhibitor, reduces the synthesis of IP subunits (105, 106) and enhances P26S-dependent protein degradation (107) | ||
| CNS disease | IP and SP status ↑ increased; ↔unchanged; ↓decreased | Effects of IP and/or SP inhibitors tested in experimental models |
| MS | Humans | |
| ↓ catalytic activities and ↔ protein levels of β1, β2, and β5 in post-mortem brain samples (gray and white matter) from MS patients (37) | ||
| ↑ immune-histochemical reactivity for β1i in the cortex and white matter of post-mortem CNS samples from MS but not young controls. In MS brain specimens β1i is detected in both glial cells and neurons and it co-localizes with plaques (108) | ||
| Experimental models | ||
| ↑β1i and β5i in the brains of Myelin Basic Peptide (MPB)-EAE mice compared, with β1i being dominantly expressed in ODCs and β5i in brain-infiltrating lymphocytes (101) | ONX 0914 ameliorates Myelin Olygodendrocyte Glycoprotein (MOG)-EAE and Proteolipid protein (PLP)-EAE by inhibiting naïve CD4+ T cells differentiation toward Th17/1 phenotype in lymph nodes and by reducing infiltration of cytokine-producing CD4+ T cells in the brain and spinal cord (98) | |
| Ex vivo, β1i and β5i from the brain of EAE mice produce a release of immunogenic MBP peptides which is 10-fold higher compared with control mice possessing low levels of IP. Ex vivo, IP-dependent release of MBP from EAE mice induces CTL-mediated targeting of ODCs (101) | PEk inhibits chymotrypsin-like activity in MBP-EAE mice brains by 70% and ameliorates demyelination pathology at a higher rate compared with PS-341 (101) | |
| ↑ amount and activities of β1i, β2i, and β5 in glia and neurons of MOG-EAE rats (102) | PEk, PS-341, and MG-132 all efficiently inhibit the release of immunogenic myelin basic protein peptides by proteasomes from MBP-EAE mice brains ex vivo (101) | |
| ↑ overall peptidase proteasome activity during the acute phase of EAE correlates with ↑levels of β1i and β5i in neurons and glia of MOG-EAE mice (109, 110) |
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| ↓ overall peptidase proteasome activity during the chronic phase of EAE correlates ↓ levels of β1, β2 in neurons and glia of MOG-EAE mice (109, 110) | Bortezomib significantly reduces clinical EAE score and disease progression in MOG-EAE mice by lowering the number of IFN-γ and IL-17 producing cells from spleens of EAE mice and NF-κB activity in the spleen and CNS of MOG-EAE mice compared with vehicle-treated controls (102) | |
| Bortezomib improves the neurological outcome and reduces the cumulative clinical score in MOG-EAE rats (102) | ||
| PS-519 reduces clinical score and relapses in PEP-Relapsing EAE mice, by ameliorating NF-κB-mediated inflammatory and demyelinating histopathology in the spinal cord, and by reducing Th1 responses in the spleen and lymph nodes from PEP-Relapsing-EAE mice compared with vehicle-treated controls (103) | ||
| AD | Humans | |
| ↓overall chymotrypsin and caspase-like activities and ↔ protein levels of β subunits in AD post-mortem brain samples (59, 111) |
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| ↓gene expression of β5 and ↑gene and protein levels of β5i and β1i in hippocampi of post-mortem AD brains (112, 113) | ||
| ↑activities of β5i, β1i, β2i in hippocampi of post-mortem AD brains correlating with tau pathology (112) | ||
| Age-related ↑of β5i and β1i in human brain tissues (114) |
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| ↑β1i and ↓β1 levels in AD affected brain regions (hippocampus) from post-mortem human samples compared with non-affected brain regions from AD patients and age-matched controls (114) | ||
| ↑ immune-reactivity for β2i and β5i in neurons and mostly in glial cells in the hippocampi of post-mortem AD brains (113) | ||
| Experimental models | ||
| Age-related ↑β5i and β1i, and ↓β5 and β1 in rats' hippocampi. LPS injections reproduces these features also in young rats, while spatial memory training reverses IP/SP ratio (115) | ONX-0914 exposure reduces pro-inflammatory signaling in ex vivo microglia isolated from AD mice, while PR-825 does not produce significant effects (112) | |
| Age-dependent ↑gene expression and protein levels of β5i and β1i in neurons and glial cells surrounding Aβ plaques in AD mice (112) |
β5i knockdown in AD mice models improves amyloid-beta (Aβ)-associated cognitive deficits by altering cytokine response in microglia but does not affect Aβ levels (117) | |
| ↑ activities of β5i, β1i, β2i, β2, and ↔ activities of β1 and β5 subunits in AD mice compared with age-matched controls (112) |
Lactacystin administration following LPS injections induces neuronal accumulation of ubiquitinated proteins, expression of pro-apoptotic markers and neurodegeneration in rats (118) | |
| ↓β5 and ↑β1i and β2i levels, and ↑trypsin-like activity in AD mice (116) | ||
| ↑gene expression and protein levels of β5i and β1i, correlates with aging and Aβ-pathology in AD mice (117) | ||
| PD and DLB | Humans | |
| ↑β5i levels and ↑chymotrypsin activity in neurons and glial cells of post-mortem brains from patients with PD and Dementia with Lewy Bodies (DLB, 119) |
ONX-0914 exposure results in greater intracellular accumulation of alpha-synuclein in vitro (119) | |
| ONX-0914 administration exacerbates 6-OHDA-induced neurotoxicity in vitro and in vivo (120) | ||
| Experimental models | ||
| ↑β5i levels in 6-OHDA mice models of PD (120) | Lactacystin or epoxomycin microinfusions within the Substantia Nigra of rats induce nigrostriatal toxicity which reproduce PD neuropathology (54) | |
| Lactacystin injected into the medial forebrain bundle in minipigs provides a model of PD with reduced DA neurotransmission, catecholamine neuron loss, microglial activation and behavioral deficits (57) | ||
| HD | Humans | |
| ↓overall chymotrypsin-like activity in the brains and fibroblast of post-mortem HD samples (60) | ||
| ↑β1i and β5i and ↓β1 and β5 levels in the degenerating and aggregate-containing neurons of post-mortem HD brains (121) | Lactacystin increases the accumulation of mutant HD exon-1 protein aggregates in vitro (122, 123) | |
| Experimental models | ||
| ↑β1i and β5i levels and ↑chymotrypsin-like activity in neurons and glia within the cortex and striatum of HD mice, with β1i localizing mainly in degenerating neurons (121) | ||
| Ischemic stroke | Humans | |
| ↑β1i, β2i, and β5i levels in plasma of ischemic stroke patients and predicts early hemorrhagic transformation in acute ischemic stroke (124) | ||
| Experimental models | ||
| ↑β1i and β5i within neurons of the parietal cortex and hippocampus in a mice model of transient focal cerebral ischemia (125) | β1i knockdown or MG-132 administration prior to MCAO ameliorate brain infraction volume in rats by reducing pro-inflammatory cytokines production and glial cells activation, with infraction volumes being smaller in β1i-silenced compared with MG-132 treated mice (104) | |
| ↑β1i and β5i in the ischemic cerebral cortex and striatum of rats with middle cerebral artery occlusion (MCAO) (104) | ||
| Epilepsy | Humans | |
| ↑β1i and β5i in neurons and glia in surgically resected temporal lobe epilepsy (TLE) hippocampi and in focal cortical dysplasia (126) | Rapamycin downregulates expression of IP subunits β1i and β5i in glial cell cultures from patients with malformations of cortical development (MCD, 38) | |
| ↑β1i, β5i, β1, and β5 levels in neurons and glia from patients with malformations of cortical development (38) and drug-resistant TLE (127) | Rapamycin ameliorates post-status epilepticus (SE) in rat models of TLE by downregulating β1i and β5i in neurons and glia. Rapamycin downregulates β1i and β5i in glial cell cultures from patients with drug-resistant TLE (127) | |
| Experimental models | ||
| ↑β5i gene expression and protein levels and ↔ levels of SP subunits in the hippocampal/entorhinal cortex from rat models of 4-aminopyridine-induced chronic epilepsy (100) |
ONX-0914 prevents the onset of seizure-like events (SLEs) in hippocampal/entorhinal cortex slices from chronic epileptic rats, and such an effect is not reproduced by PR-825 (100) | |
| ↑β1i and β5i levels correlate with seizure frequency in a rat model of TLE (127) | ||