Genetic Ablation of EWS RNA Binding Protein 1 (EWSR1) Leads to Neuroanatomical Changes and Motor Dysfunction in Mice

A recent study reveals that missense mutations of EWSR1 are associated with neurodegenerative disorders such as amyotrophic lateral sclerosis, but the function of wild-type (WT) EWSR1 in the central nervous system (CNS) is not known yet. Herein, we investigated the neuroanatomical and motor function changes in Ewsr1 knock out (KO) mice. First, we quantified neuronal nucleus size in the motor cortex, dorsal striatum and hippocampus of three different groups: WT, heterozygous Ewsr1 KO (+/−), and homozygous Ewsr1 KO (−/−) mice. The neuronal nucleus size was significantly smaller in the motor cortex and striatum of homozygous Ewsr1 KO (−/−) mice than that of WT. In addition, in the hippocampus, the neuronal nucleus size was significantly smaller in both heterozygous Ewsr1 KO (+/−) and homozygous Ewsr1 KO (−/−) mice. We then assessed motor function of Ewsr1 KO (−/−) and WT mice by a tail suspension test. Both forelimb and hindlimb movements were significantly increased in Ewsr1 KO (−/−) mice. Lastly, we performed immunohistochemistry to examine the expression of TH, DARPP-32, and phosphorylated (p)-DARPP-32 (Thr75) in the striatum and substantia nigra, which are associated with dopaminergic signaling. The immunoreactivity of TH and DARPP-32 was decreased in Ewsr1 KO (−/−) mice. Together, our results suggest that EWSR1 plays a significant role in neuronal morphology, dopaminergic signaling pathways, and motor function in the CNS of mice.

Effects and molecular mechanism of chitosan-coated levodopa nanoliposomes on behavior of dyskinesia rats

BACKGROUND: Chitosan, the N-deacetylated derivative of chitin, is a cationic polyelectrolyte due to the presence of amino groups, one of the few occurring in nature. The use of chitosan in protein and drug delivery systems is being actively researched and reported in the literature RESULTS: In this study, we used chitosan-coated levodopa liposomes to investigate the behavioral character and the expression of phosphorylated extracellular signal-regulated kinase (ERK1/2), dopamine- and cAMP-regulated phos-phoprotein of 32 kDa (DARPP-32) and FosB/AFosB in striatum of rat model of levodopa-induced dyskinesia (LID). We found that scores of abnormal involuntary movement (AIM) decreased significantly in liposome group (P < 0.05), compared with levodopa group. Levels of phospho-ERK1/2, phospho-Thr34 DARPP-32 and FosB/AFosB in striatum decreased significantly in liposome group lesion side compared with levodopa group (P < 0.05). However, both of two groups above have significantly differences compared with the control group (P < 0.05). CONCLUSION: Chitosan-coated levodopa liposomes may be useful in reducing dyskinesias inducing for Parkinson disease. The mechanism might be involved the pathway of signaling molecular phospho-ERK1/2, phospho-Thr34 DARPP-32 and AFosB in striatum

The evolutionary strata of DARPP-32 tail implicates hierarchical functional expansion in higher vertebrates.

DARPP-32 (dopamine and adenosine 3′,5′-monophosphate-regulated phosphoprotein of 32 kDa), which belongs to PPP1R1 gene family, is known to act as an important integrator in dopamine-mediated neurotransmission via the inhibition of protein phosphatase-1 (PP1). Besides its neuronal roles, this protein also behaves as a key player in pathological and pharmacological aspects. Use of bioinformatics and phylogenetics approaches to further characterize the molecular features of DARPP-32 can guide future works. Predicted phosphorylation sites on DARPP-32 show conservation across vertebrates. Phylogenetics analysis indicates evolutionary strata of phosphorylation site acquisition at the C-terminus, suggesting functional expansion of DARPP-32, where more diverse signalling cues may involve in regulating DARPP-32 in inhibiting PP1 activity. Moreover, both phylogenetics and synteny analyses suggest de novo origination of PPP1R1 gene family via chromosomal rearrangement and exonization.

An updated review of the research on Her-2-targeted antibody resistance mechanisms / 中国癌症杂志

Human epidermal growth factor receptor 2(Her-2),which is often over-expressed in 20%-25% of invasive breast cancer patients,is associated with an aggressive tumor phenotype and therefore,a reduced survival rate.As a widely clinically applied Her-2-targeted monoclonal antibody,herceptin,when combined with chemotherapy,significantly increases the survival time of patients without tumors.However,the majority of the cancers that initially respond positively to herceptin begin to counteract against the treatment within just 1 year.This study described several important and well-known mechanisms as well as the updates and advancement in this field.These mechanisms include over-activation of the P13K/AKT pathway,abnormal expression in the EGFR family and their ligands,the masking of the Her-2 receptor,herceptin,activation of PI3K/AKT via an alternative pathway,over-expression of Darpp-32 and t-Darpp.autophagy of tumor cells and over-expression of HSP27,and more.

Localization of dopamine- and cAMP-regulated phosphoprotein in mouse kidney / 第三军医大学学报

Objective To investigate the expression and localization of dopamine- and cAMP-regulated phosphoprotein of 32 000 (DARPP-32) in mouse kidney tissue. Methods The cellular localization of DARPP-32 in mouse kidney tissue was detected by immunoblot and immunohistochemistry. Results DARPP-32-like immunoreactivity was detected in the medullary thick ascending limb of the loop of Henle, the cortical proximal convoluted tubule, and collecting ducts in medullary rays. The renal tubules were enriched of Na+, K+-ATPase for sodium reabsorption. Conclusion The participation of DARPP-32 is a likely crucial step of the signal-transduction pathway of dopamine regulation on sodium reabsorption in renal tubule cells.