[Abstract unavailable

DJ-1, originally identified as an oncogene product, is a protein with various functions in cellular transformation, oxidative stress response, and transcriptional regulation. Although previous studies suggest that DJ-1 is cytoprotective, the mechanism by which DJ-1 exerts its survival functions remains largely unknown. Here we show that DJ-1 exerts its cytoprotection through inhibiting p53-Bax-caspase pathway. DJ-1 interacts with p53 in vitro and in vivo. Overexpression of DJ-1 decreases the expression of Bax and inhibits caspase activation, whereas knockdown of DJ-1 increases Bax protein levels and accelerates caspase-3 activation and cell death induced by UV exposure. Our data provide evidence that the protective effects of DJ-1 on apoptosis are associated with its ability of decreasing Bax level through inhibiting p53 transcriptional activity.

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Mutations in PTEN-induced kinase 1 (PINK1) gene cause PARK6 familial Parkinsonism, and loss of the stability of PINK1 may also contribute to sporadic Parkinson's disease (PD). Degradation of PINK1 occurs predominantly through the ubiquitin proteasome system (UPS), however, to date, few of the proteins have been found to regulate the degradation of PINK1. Using the yeast two-hybrid system and pull-down methods, we identified bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly interacted with PINK1. We showed that BAG5 stabilized PINK1 by decreasing the ubiquitination of PINK1. Interestingly, BAG5 rescued MPP+- and rotenone-induced mitochondria dysfunction by up-regulating PINK1 in vitro. In PINK1-null mice and MPTP-treated mice, BAG5 significantly increased in the substantia nigra pars compacta (SNpc) although PINK1 was decreased. Our findings indicated that BAG5, as a key protein to stabilize PINK1, is a promising therapeutic tool for preventing mitochondrial dysfunction following oxidative stress.

BackgroundTransmembrane protein 108 (Tmem108) is a risk gene of psychiatric diseases including schizophrenia, bipolar disorder and major depression disorder. However, the pathophysiological mechanisms of Tmem108 are largely unknown.ResultsHere we investigated the pathophysiological function of Tmem108 in the hippocampal dentate gyrus by using Tmem108 mutant mice. Tmem108 highly expressed in the dentate gyrus and CA3 of the hippocampus. Dentate gyrus is a brain region where adult neurogenesis occurs, and aberrant adult neurogenesis in dentate gyrus has been implicated in major depression disorder. Indeed, Tmem108 mutant mice had lower immobility than wild type mice in tail suspension test and forced swimming test. BrdU and anti-Ki67 antibody staining indicated that adult neurogenesis of the hippocampal dentate gyrus region decreased in Tmem108 mutant mice. qPCR results showed that expression of Axin2, DISC1 and β-Catenin, three dentate gyrus adult neurogenesis related genes in Wnt/β-Catenin signaling pathway, decreased in Tmem108 mutant mice. Furthermore, Tmem108 enhanced free β-Catenin level in dual luciferase assay.ConclusionsThus, our data suggest that Tmem108 increases adult neurogenesis and plays a complexity role in psychiatric disorders.

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Sumoylation is an important post-translational modification, which is also involved in the pathogenesis of many neurodegenerative diseases. We previously reported that DJ-1 decreases Bcl-2 associated X protein expression through repressing p53 transcriptional activity. Here we show that DJ-1(K130R), the non-sumoylatable mutant form of DJ-1, shifts from nucleus to cytoplasm, fails to repress p53 transcriptional activity and loses its protective function against ultraviolet induced cell death. Our findings suggest that sumoylation is critical for DJ-1 to repress p53 transcriptional activity.

Neurotrophic factor NRG1 and its receptor ErbB4 play a role in GABAergic circuit assembly during development. ErbB4 null mice possess fewer interneurons, have decreased GABA release, and show impaired behavior in various paradigms. In addition, NRG1 and ErbB4 have also been implicated in regulating GABAergic transmission and plasticity in matured brains. However, current ErbB4 mutant strains are unable to determine whether phenotypes in adult mutant mice result from abnormal neural development. This important question, a glaring gap in understanding NRG1–ErbB4 function, was addressed by using two strains of mice with temporal control of ErbB4 deletion and expression, respectively. We found that ErbB4 deletion in adult mice impaired behavior and GABA release but had no effect on neuron numbers and morphology. On the other hand, some deficits due to the ErbB4 null mutation during development were alleviated by restoring ErbB4 expression at the adult stage. Together, our results indicate a critical role of NRG1–ErbB4 signaling in GABAergic transmission and behavior in adulthood and suggest that restoring NRG1–ErbB4 signaling at the postdevelopmental stage might benefit relevant brain disorders.