Guanghui Wang

University of Science and Technology of China, Hefei, Anhui Sheng, China

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Publications (34)124.27 Total impact

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    ABSTRACT: Poly-ubiquitinated protein aggregate formation is the most striking hallmark of various neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. Mutations of many ubiquitin-associated proteins involved in the regulation of protein aggregation, such as SQSTM1/p62 (p62), parkin, and VCP, are closely linked to neurodegeneration. B-cell lymphoma 2 (Bcl-2) is a key regulator in autophagy, apoptosis, and mitochondria quality control in many cell types including neurons, and it plays important roles in the pathogenesis of neurodegenerative diseases mentioned above. Our previous work showed that Bcl-2 can directly bind to p62, and here we report that Bcl-2 directly interacts with the N-terminus of p62, but not the C-terminus (UBA domain). Interestingly and importantly, Bcl-2 affects the affinity of p62 to poly-ubiquitin chains and suppresses the aggregation of poly-ubiquitinated proteins such as mutant huntingtin associated with Huntington's disease. Our study reveals a role of Bcl-2 that involves in the regulation of misfolded proteins.
    Molecular neurobiology. 10/2014;
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    ABSTRACT: Background Phosphodiesterase (PDE) 10A is selectively expressed in medium spiny neurons of the striatum. Nucleus accumbens (NAc) is a key region that mediates drug reward and addiction-related behaviors. To investigate the potential role of PDE10A in the reinforcement properties of morphine, we tested the effect of MP-10, a selective inhibitor of PDE10A, on acquisition, expression, and extinction of morphine-induced conditioned place preference (CPP).ResultsThe results show that 2.5 mg/kg MP-10, administered subcutaneously, significantly inhibited the acquisition of morphine-induced CPP. The same dose of MP-10 alone did not result in the CPP. Moreover, MP-10 did not alter the expression of morphine-induced CPP, but did accelerate the extinction of morphine-induced CPP. Additionally, chronic treatment with 2.5 mg/kg MP-10 decreased expression of phosphorylated CREB (pCREB), activated cAMP response element binding protein, in dorsomedial striatum, in shell of NAc, and in anterior cingulate cortex (ACC) as well as decreased expression of ¿FosB in the shell of NAc and ACC.Conclusion The results suggest that inhibition of PDE10A may have therapeutic potential in the treatment of opioid addiction.
    Molecular brain. 09/2014; 7(1):70.
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    ABSTRACT: Abstract The expansion of a polyglutamine domain in the protein ataxin3 causes spinocerebellar ataxia type-3 (SCA3). However, there is little information to date about the upstream proteins in the ubiquitin-proteasome system of pathogenic ataxin3-80Q. Here, we report that BAG2 (Bcl-2 associated athanogene family protein 2) and BAG5 (Bcl-2-associated athanogene family protein 5) stabilise pathogenic ataxin3-80Q by inhibiting its ubiquitination as determined based on western blotting and co-immunofluorescence experiments. The association of the BAG2 and BAG5 proteins with pathogenic ataxin3-80Q strengthens the important roles of the BAG family in neurodegenerative diseases.
    The International journal of neuroscience. 07/2014;
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    ABSTRACT: 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.
    PLoS ONE 01/2014; 9(1):e86276. · 3.53 Impact Factor
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    ABSTRACT: The cellular protein quality control system in association with aggresome formation contributes to protecting cells against aggregation-prone protein-induced toxicity. p62/Sequestosome 1 (p62) is a multifunctional protein which plays an important role in protein degradation and aggregation. Although poly-ubiquitination is usually required for p62-mediated protein degradation and aggresome formation, several p62 substrates are processed to form aggregate in an ubiquitination-independent manner. In this study we demonstrate that p62 directly interacts with pathogenic Machado Joseph Disease (MJD)-associated protein ataxin-3 with polyglutamine (polyQ) expansion. Moreover, p62 could regulate the aggresome formation of pathogenic ataxin-3 and protect cells against pathogenic ataxin-3-induced cell death.
    International Journal of Molecular Sciences 01/2014; 15(9):14997-15010. · 2.46 Impact Factor
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    ABSTRACT: Mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause an autosomal recessive form of Parkinson disease (PD). Thus far, little is known about what can regulate the ubiquitin proteasome pathway of PINK1. Here, we report BAG2 (Bcl-2-associated athanogene family protein 2), a member of the BAG family, which directly binds with and stabilises PINK1 by decreasing its ubiquitination. Moreover, we found that BAG2 also binds with the pathogenic R492X PINK1 mutation directly and more tightly. Moreover, BAG2 stabilises the R492X PINK1 mutation by decreasing its ubiquitination to a greater extent than the wild-type species. Our data correlate BAG2 to PINK1 for the first time, strengthening the important role of BAG2 in PD-related neurodegeneration.
    Biochemical and Biophysical Research Communications 11/2013; 441(2):488-92. · 2.28 Impact Factor
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    ABSTRACT: Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder associated with polyglutamine (polyQ) protein ataxin-3. Ataxin-3 is a multi-functional protein, but the precise mechanisms underlying the cellular functions of ataxin-3 remain to be elucidated. Here we demonstrate that ataxin-3 plays a protective role against cellular oxidative stress induced by H2O2 in a Bcl-XL-dependent manner. Ataxin-3 directly interacts with Bcl-XL. The N-terminus of ataxin-3 and the C-terminus of Bcl-XL are essential for the interaction. Ataxin-3 promotes the interaction between Bcl-XL and Bax, but does not affect the ubiquitination and degradation of Bcl-XL. Our data suggest that ataxin-3 plays an important role in regulating the Bcl-XL-Bax-mediated anti-oxidative response by modulating the interaction between Bcl-XL and Bax.
    Neuroscience 04/2013; · 3.12 Impact Factor
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    ABSTRACT: SKF83959, an atypical dopamine receptor-1(D(1) receptor) agonist, has showed many D(1) receptor-independent effects, such as neuroprotection, blockade of Na(+) channel, and promotion of spontaneous glutamate release, which somehow resemble the effects of the sigma-1 receptor activation. In the present work, we explored the potential modulation of SKF83959 on the sigma-1 receptor. The results indicated that SKF835959 dramatically promoted the binding of (3)H(+)-pentazocine (a selective sigma-1 receptor agonist) to the sigma-1 receptor in brain and liver tissues, but produced no effect on (3)H-progesterone binding (a sigma-1 receptor antagonist). The saturation assay and the dissociation kinetics assay confirmed the allosteric effect. We further demonstrated that the SKF83959 analogs, such as SCH22390 and SKF38393, also showed the similar allosteric effect on the sigma-1 receptor in the liver tissue but not in the brain tissue. Moreover, all three tested chemicals elicited no significant effect on (3)H-1,3-di(2-tolyl)-guanidine((3)H-DTG) binding to the sigma-2 receptor. The present data uncovered a new role of SKF83959 and its analogs on the sigma-1 receptor, which, in turn, may reveal the underlying mechanism for the D(1) receptor-independent effect of the drug.
    Molecular pharmacology 01/2013; · 4.53 Impact Factor
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    Feng Gao, Dong Chen, Qingsong Hu, Guanghui Wang
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    ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disease. Although its pathogenesis is still unclear, increasing evidence suggests that mitochondrial dysfunction induced by environmental toxins, such as mitochondrial complex I inhibitors, plays a significant role in the disease process. The microglia in PD brains are highly activated, and inflammation is also an essential element in PD pathogenesis. However, the means by which these toxins activate microglia is still unclear. In the present study, we found that rotenone, a mitochondrial complex I inhibitor, could directly activate microglia via the nuclear factor kappa B (NF-κB) signaling pathway, thereby inducing significantly increased expression of inflammatory cytokines. We further observed that rotenone induced caspase-1 activation and mature IL-1β release, both of which are strictly dependent on p38 mitogen-activated protein kinase (MAPK). The activation of p38 is associated with the presence of reactive oxygen species (ROS) produced by rotenone. Removal of these ROS abrogated the activation of the microglia. Therefore, our data suggest that the environmental toxin rotenone can directly activate microglia through the p38 MAPK pathway.
    PLoS ONE 01/2013; 8(8):e72046. · 3.53 Impact Factor
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    ABSTRACT: Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia.
    PLoS ONE 01/2013; 8(12):e81884. · 3.53 Impact Factor
  • Zheng Ying, Hongfeng Wang, Guanghui Wang
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    ABSTRACT: Neurodegenerative diseases are severe disorders characterized by progressive neurodegeneration in specific regions of brain. The ubiquitin-proteasome system (UPS) is closely linked to neuro-degeneration. Impairment and dysregulation of the UPS components are frequently observed. Moreover, toxin-induced neurodegeneration produces neuronal cell death accompanied by decreased UPS function. These studies suggest an involvement of the UPS in these diseases. In this review, we summarize the changes to UPS components in neurodegenerative diseases and the association between the UPS and disease pathology. Dysfunction of the UPS results in the abnormal accumulation of proteins; thus, the UPS plays a critical role in disease pathogenesis. Drugs targeting specific components of the UPS may provide promising strategies for disease treatment.
    Current pharmaceutical design 11/2012; · 4.41 Impact Factor
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    ABSTRACT: Mutations or deletions in DJ-1/PARK7 gene are causative for recessive forms of early onset Parkinson's disease (PD). Wild-type DJ-1 has cytoprotective roles against cell death through multiple pathways. The most commonly studied mutant DJ-1(L166P) shifts its subcellular distribution to mitochondria and renders cells more susceptible to cell death under stress stimuli. We previously reported that wild-type DJ-1 binds to Bcl-XL and stabilizes it against ultraviolet B (UVB) irradiation-induced rapid degradation. However, the mechanisms by which mitochondrial DJ-1(L166P) promotes cell death under death stimuli are largely unknown. We show that DJ-1(L166P) is more prone to localize in mitochondria and it binds to Bcl-XL more strongly than wild-type DJ-1. In addition, UVB irradiation significantly promotes DJ-1(L166P) translocation to mitochondria and binding to Bcl-XL. DJ-1(L166P) but not wild-type DJ-1 dissociates Bax from Bcl-XL, thereby leading to Bax enrichment at outer mitochondrial membrane and promoting mitochondrial apoptosis pathway in response to UVB irradiation. Our findings suggest that wild-type DJ-1 protects cells and DJ-1(L166P) impairs cells by differentially regulating mitochondrial Bax/Bcl-XL functions.
    Molecular Neurodegeneration 08/2012; 7:40. · 4.01 Impact Factor
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    ABSTRACT: HS-1-associated protein X-1 (Hax-1), is a multifunctional protein that has sequence homology to Bcl-2 family members. HAX-1 knockout animals reveal that it plays an essential protective role in the central nervous system against various stresses. Homozygous mutations in the HAX-1 gene are associated with autosomal recessive forms of severe congenital neutropenia along with neurological symptoms. The protein level of Hax-1 has been shown to be regulated by cellular protease cleavage or by transcriptional suppression upon stimulation. Here, we report a novel post-translational mechanism for regulation of Hax-1 levels in mammalian cells. We identified that PEST sequence, a sequence rich in proline, glutamic acid, serine and threonine, is responsible for its poly-ubiquitination and rapid degradation. Hax-1 is conjugated by K48-linked ubiquitin chains and undergoes a fast turnover by the proteasome system. A deletion mutant of Hax-1 that lacks the PEST sequence is more resistant to the proteasomal degradation and exerts more protective effects against apoptotic stimuli than wild type Hax-1. Our data indicate that Hax-1 is a short-lived protein and that its PEST sequence dependent fast degradation by the proteasome may contribute to the rapid cellular responses upon different stimulations.
    BMC Cell Biology 07/2012; 13:20. · 2.81 Impact Factor
  • Hongfeng Wang, Zheng Ying, Guanghui Wang
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    ABSTRACT: Polyubiquitination of misfolded proteins, especially K63-linked polyubiquitination, is thought to be associated with the formation of inclusion bodies. However, it is not well explored whether appropriate editing of the different types of ubiquitin linkages by deubiquitinating enzymes (DUBs) affects the dynamics of inclusion bodies. In this study, we report that a specific DUB, ataxin-3, is required for the efficient recruitment of the neurodegenerative disease-associated protein copper-zinc superoxide dismutase (SOD1) to aggresomes. The overexpression of ataxin-3 promotes mutant SOD1 aggresome formation by trimming K63-linked polyubiquitin chains. Moreover, knockdown of ataxin-3 decreases mutant SOD1 aggresome formation and increases cell death induced by mutant SOD1. Thus, our data suggest that the sequestration of misfolded SOD1 into aggresomes, which is driven by ataxin-3, plays an important role in attenuating protein misfolding-induced cell toxicity.
    Journal of Biological Chemistry 07/2012; 287(34):28576-85. · 4.65 Impact Factor
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    Haigang Ren, Kai Fu, Jun Fan, Guanghui Wang
    Molecular Neurodegeneration 02/2012; 7 Suppl 1:L16. · 4.01 Impact Factor
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    ABSTRACT: Inflammation in Parkinson's disease is closely associated with disease pathogenesis. Mutations in Omi, which encodes the protease Omi, are linked to neurodegeneration and Parkinson's disease in humans and in mouse models. The severe neurodegeneration and neuroinflammation that occur in mnd2 (motor neuron degeneration 2) mice result from loss of the protease activity of Omi by the point mutation S276C; however, the substrates of Omi that induce neurodegeneration are unknown. We showed that Omi was required for the production of inflammatory molecules by microglia, which are the resident macrophages in the central nervous system. Omi suppressed the activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1 and 2 (ERK1/2) by cleaving the upstream kinase MEK1 (mitogen-activated or extracellular signal-regulated protein kinase kinase 1). Knockdown of Omi in microglial cell lines led to activation of ERK1/2 and resulted in degradation of IκBα [α inhibitor of nuclear factor κB (NF-κB)], resulting in NF-κB activation and the expression of genes encoding inflammatory molecules, such as tumor necrosis factor-α and inducible nitric oxide synthase. The production of inflammatory molecules induced by the knockdown of Omi was blocked by the MEK1-specific inhibitor U0126. Furthermore, expression of the protease-deficient S276C Omi mutant in a microglial cell line had no effect on MEK1 cleavage or ERK1/2 activation. In the brains of mnd2 mice, we observed increased transcription of several genes encoding inflammatory molecules, as well as activation of astrocytes and microglia. Therefore, our study demonstrates that Omi is an intrinsic cellular factor that inhibits neuroinflammation.
    Science Signaling 01/2012; 5(238):ra61. · 7.65 Impact Factor
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    ABSTRACT: Parkinson disease (PD)- and cancer-associated protein, DJ-1, mediates cellular protection via many signaling pathways. Deletions or mutations in the DJ-1 gene are directly linked to autosomal recessive early-onset PD. DJ-1 has potential roles in mitochondria. Here, we show that DJ-1 increases its mitochondrial distribution in response to ultraviolet B (UVB) irradiation and binds to Bcl-X(L). The interactions between DJ-1 and Bcl-X(L) are oxidation-dependent. DJ-1(C106A), a mutant form of DJ-1 that is unable to be oxidized, binds Bcl-X(L) much less than DJ-1 does. Moreover, DJ-1 stabilizes Bcl-X(L) protein level by inhibiting its ubiquitination and degradation through ubiquitin proteasome system (UPS) in response to UVB irradiation. Furthermore, under UVB irradiation, knockdown of DJ-1 leads to increases of Bcl-X(L) ubiquitination and degradation upon UVB irradiation, thereby increasing mitochondrial Bax, caspase-3 activation and PARP cleavage. These data suggest that DJ-1 protects cells against UVB-induced cell death dependent on its oxidation and its association with mitochondrial Bcl-X(L).
    Journal of Biological Chemistry 08/2011; 286(40):35308-17. · 4.65 Impact Factor
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    ABSTRACT: Familial encephalopathy with neuroserpin inclusion bodies is a neurodegenerative disorder characterized by the accumulation of neuroserpin polymers in the endoplasmic reticulum (ER) of cortical and subcortical neurons in the CNS because of neuroserpin point mutations. ER-associated degradation (ERAD) is involved in mutant neuroserpin degradation. In this study, we demonstrate that two ER-associated E3 ligases, Hrd1 and gp78, are involved in the ubiquitination and degradation of mutant neuroserpin. Overexpression of Hrd1 and gp78 decreases the mutant neuroserpin protein level, whereas Hrd1 and gp78 knockdown increases mutant neuroserpin stability. Moreover, ERAD impairment by mutant valosin-containing protein increases the mutant neuroserpin protein level and aggregate formation. Thus, these findings identify mutant neuroserpin as an ERAD target and show that Hrd1 and gp78 mediate mutant neuroserpin turnover through the ERAD pathway.
    Journal of Biological Chemistry 06/2011; 286(23):20835-44. · 4.65 Impact Factor
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    ABSTRACT: Parkin is an E3 ubiquitin ligase that mediates the ubiquitination of protein substrates. The mutations in the parkin gene can lead to a loss of function of parkin and cause autosomal recessive juvenile onset parkinsonism. Recently, parkin was reported to be involved in the regulation of mitophagy. Here, we identify the Bcl-2, an anti-apoptotic and autophagy inhibitory protein, as a substrate for parkin. Parkin directly binds to Bcl-2 via its C terminus and mediates the mono-ubiquitination of Bcl-2, which increases the steady-state levels of Bcl-2. Overexpression of parkin, but not its ligase-deficient forms, decreases autophagy marker LC3 conversion, whereas knockdown of parkin increases LC3 II levels. In HeLa cells, a parkin-deficient cell line, knockdown of parkin does not change LC3 conversion. Moreover, overexpression of parkin enhances the interactions between Bcl-2 and Beclin 1. Our results provide evidence that parkin mono-ubiquitinates Bcl-2 and regulates autophagy via Bcl-2.
    Journal of Biological Chemistry 12/2010; 285(49):38214-38223. · 4.65 Impact Factor
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    ABSTRACT: Autophagy mediates cellular self-digestion to degrade cytoplasmic proteins and organelles and plays important roles in tumorigenesis. DJ-1 is an oncogene product in association with cancers and tumorigenesis. In this study, we show that knockdown of DJ-1 induces autophagy through activating JNK pathway to promote Beclin 1 transcription, whereas overexpression of DJ-1 inhibits these processes. Moreover, inhibition of JNK pathway by SP600125 blocks autophagy activation and p62 degradation induced by knockdown of DJ-1. Our findings suggest that DJ-1 regulates autophagy in a JNK-dependent manner. Thus, the involvement of DJ-1 in autophagy regulation may be involved in tumorigenesis.
    Cancer letters 11/2010; 297(1):101-8. · 5.02 Impact Factor