| 1 | Biol. Psychiatry 2012 May 71: 906-14 |
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| PMID | 22458949 |
| Title | Abnormalities of the Duo/Ras-related C3 botulinum toxin substrate 1/p21-activated kinase 1 pathway drive myosin light chain phosphorylation in frontal cortex in schizophrenia. |
| Abstract | Recent studies on GTPases have suggested that reduced Duo and cell division cycle 42 (Cdc42) transcript expression is involved in dendritic spine loss inschizophrenia. In murine models, Duo and Cdc42 phosphorylate p21-activated kinase 1 (PAK1), which modifies the activity of regulatory myosin light chain (MLC) and cofilin by altering their phosphorylation. Therefore, we hypothesized that inschizophreniaabnormal Duo and Cdc42 expression result in changes in MLC and/or cofilin phosphorylation, which might alter actin cytoskeleton dynamics underlying dendritic spine maintenance. We performed Western blot protein expression analysis in postmortem brains from patients diagnosed withschizophreniaand a comparison group. We focused our studies in the anterior cingulate cortex (ACC; n = 33 comparison group; n = 36schizophrenia) and dorsolateral prefrontal cortex (DLPFC; n = 29 comparison group; n = 35schizophrenia). In both ACC and DLPFC, we found a reduction of Duo expression andPAK1phosphorylation inschizophrenia. Cdc42 protein expression was decreased in ACC but not in DLPFC. In ACC, we observed decreasedPAK1phosphorylation and increased MLC phosphorylation (pMLC), whereas in DLPFC pMLC remained unchanged. These data suggest a novel mechanism that might underlie dendritic spine loss inschizophrenia. The increase in pMLC seen in ACC might be associated with dendritic spine shrinkage. The lack of an effect on pMLC in DLPFC suggests that inschizophreniaPAK1downstream pathways are differentially affected in these cortical areas. |
| SCZ Keywords | schizophrenia |
| 2 | PLoS ONE 2013 -1 8: e59458 |
| PMID | 23613712 |
| Title | PAK1 protein expression in the auditory cortex of schizophrenia subjects. |
| Abstract | Deficits in auditory processing are among the best documented endophenotypes inschizophrenia, possibly due to loss of excitatory synaptic connections. Dendritic spines, the principal post-synaptic target of excitatory projections, are reduced inschizophrenia. p21-activated kinase 1 (PAK1) regulates both the actin cytoskeleton and dendritic spine density, and is a downstream effector of both kalirin and CDC42, both of which have altered expression inschizophrenia. This study sought to determine if there is decreased auditory cortexPAK1protein expression inschizophreniathrough the use of quantitative western blots of 25schizophreniasubjects and matched controls. There was no significant change inPAK1level detected in theschizophreniasubjects in our cohort.PAK1protein levels within subject pairs correlated positively with prior measures of total kalirin protein in the same pairs.PAK1level also correlated with levels of a marker of dendritic spines, spinophilin. These latter two findings suggest that the lack of change inPAK1level inschizophreniais not due to limited sensitivity of our assay to detect meaningful differences inPAK1protein expression. Future studies are needed to evaluate whether alterations inPAK1phosphorylation states, or alterations in protein expression of other members of the PAK family, are present inschizophrenia. |
| SCZ Keywords | schizophrenia |
| 3 | Phytother Res 2014 May 28: 656-72 |
| PMID | 23943274 |
| Title | Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity. |
| Abstract | Over 35?years research on PAKs, RAC/CDC42(p21)-activated kinases, comes of age, and in particularPAK1has been well known to be responsible for a variety of diseases such as cancer (mainly solid tumors), Alzheimer's disease, acquired immune deficiency syndrome and other viral/bacterial infections, inflammatory diseases (asthma and arthritis), diabetes (type 2), neurofibromatosis, tuberous sclerosis, epilepsy, depression,schizophrenia, learning disability, autism, etc. Although several distinct syntheticPAK1阻滞剂最近开发的,不FDA-approvedPAK1blockers are available on the market as yet. Thus, patients suffering from thesePAK1-dependent diseases have to rely on solely a variety of herbal therapeutics such as propolis and curcumin that blockPAK1without affecting normal cell growth. Furthermore, several recent studies revealed that some of these herbal therapeutics significantly extend the lifespan of nematodes (C. elegans) and fruit flies (Drosophila), andPAK1-deficient worm lives longer than the wild type. Here, I outline mainly pathological phenotypes of hyper-activatedPAK1and a list of herbal therapeutics that blockPAK1, but cause no side (harmful) effect on healthy people or animals. |
| SCZ Keywords | schizophrenia |
| 4 | Biol. Psychiatry 2015 Dec 78: 775-85 |
| PMID | 25981171 |
| Title | Altered expression of CDC42 signaling pathway components in cortical layer 3 pyramidal cells in schizophrenia. |
| Abstract | Cognitive dysfunction inschizophreniais associated with a lower density of dendritic spines on deep layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC). These alterations appear to reflect dysregulation of the actin cytoskeleton required for spine formation and maintenance. Consistent with this idea, altered expression of genes in the cell division cycle 42 (CDC42)-CDC42 effector protein (CDC42EP) signaling pathway, a key organizer of the actin cytoskeleton, was previously reported in DLPFC gray matter from subjects withschizophrenia. We examined the integrity of the CDC42-p21-activated serine/threonine protein kinases (PAK)-LIM domain-containing serine/threonine protein kinases (LIMK) signaling pathway inschizophreniain a layer-specific and cell type-specific fashion in DLPFC deep layer 3. Using laser microdissection, samples of DLPFC deep layer 3 were collected from 56 matched pairs of subjects withschizophrenia和比较对象,CDC42-PAK-L水平IMK pathway messenger RNAs were measured by quantitative polymerase chain reaction. These same transcripts also were quantified by microarray in samples of individually microdissected deep layer 3 pyramidal cells from a subset of the same subjects and from monkeys exposed to antipsychotics. Relative to comparison subjects, CDC42EP4, LIMK1, LIMK2, ARHGDIA, and PAK3 messenger RNA levels were significantly upregulated in subjects withschizophreniain laminar and cellular samples. In contrast, CDC42 andPAK1messenger RNA levels were significantly downregulated specifically in deep layer 3 pyramidal cells. These differences were not attributable to psychotropic medications or other comorbid factors. Findings from the present and prior studies converge on synergistic alterations in CDC42 signaling pathway that could destabilize actin dynamics and produce spine deficits preferentially in deep layer 3 pyramidal cells inschizophrenia. |
| SCZ Keywords | schizophrenia |