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Article ; Online: Proteomic Signaling of Dual-Specificity Phosphatase 4 (DUSP4) in Alzheimer's Disease.

Wang, Erming / Pan, Allen L / Bagchi, Pritha / Rangaraju, Srikant / Seyfried, Nicholas T / Ehrlich, Michelle E / Salton, Stephen R / Zhang, Bin

Biomolecules

2024 Volume 14, Issue 1

Abstract: DUSP4 is a member of the DUSP (dual-specificity phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimer's disease (AD). In this study, ... ...

Abstract	DUSP4 is a member of the DUSP (dual-specificity phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimer's disease (AD). In this study, we utilized the stereotactic delivery of adeno-associated virus (AAV)-DUSP4 to overexpress DUSP4 in the dorsal hippocampus of 5xFAD and wildtype (WT) mice, then used mass spectrometry (MS)-based proteomics along with the label-free quantification to profile the proteome and phosphoproteome in the hippocampus. We identified protein expression and phosphorylation patterns modulated in 5xFAD mice and examined the sex-specific impact of DUSP4 overexpression on the 5xFAD proteome/phosphoproteome. In 5xFAD mice, a substantial number of proteins were up- or down-regulated in both male and female mice in comparison to age and sex-matched WT mice, many of which are involved in AD-related biological processes, such as activated immune response or suppressed synaptic activities. Many proteins in pathways, such as immune response were found to be suppressed in response to DUSP4 overexpression in male 5xFAD mice. In contrast, such a shift was absent in female mice. For the phosphoproteome, we detected an array of phosphorylation sites regulated in 5xFAD compared to WT and modulated via DUSP4 overexpression in each sex. Interestingly, 5xFAD- and DUSP4-associated phosphorylation changes occurred in opposite directions. Strikingly, both the 5xFAD- and DUSP4-associated phosphorylation changes were found to be mostly in neurons and play key roles in neuronal processes and synaptic functions. Site-centric pathway analysis revealed that both the 5xFAD- and DUSP4-associated phosphorylation sites were enriched for a number of kinase sets in females but only a limited number of sets of kinases in male mice. Taken together, our results suggest that male and female 5xFAD mice responded to DUSP4 overexpression via shared and sex-specific molecular mechanisms, which might underly similar reductions in amyloid pathology in both sexes while learning deficits were reduced in only females with DUSP4 overexpression. Finally, we validated our findings with the sex-specific AD-associated proteomes in human cohorts and further developed DUSP4-centric proteomic network models and signaling maps for each sex.
MeSH term(s)	Animals ; Female ; Humans ; Male ; Mice ; Alzheimer Disease/genetics ; Dependovirus ; Dual-Specificity Phosphatases/genetics ; Mitogen-Activated Protein Kinase Phosphatases/genetics ; Proteome ; Proteomics ; Signal Transduction
Chemical Substances	Dual-Specificity Phosphatases (EC 3.1.3.48) ; DUSP4 protein, human (EC 3.1.3.48) ; Mitogen-Activated Protein Kinase Phosphatases (EC 3.1.3.16) ; Proteome ; MKP2 protein, mouse (EC 3.1.3.48)
Language	English
Publishing date	2024-01-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom14010066
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Proteomic signaling of dual specificity phosphatase 4 (DUSP4) in Alzheimer's disease.

Wang, Erming / Pan, Allen L / Bagchi, Pritha / Ranjaraju, Srikant / Seyfried, Nicholas T / Ehrlich, Michelle E / Salton, Stephen R / Zhang, Bin

bioRxiv : the preprint server for biology

2023

Abstract: DUSP4 is a member of the DUSP (Dual-Specificity Phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimer's disease (AD). In this study, ... ...

Abstract	DUSP4 is a member of the DUSP (Dual-Specificity Phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimer's disease (AD). In this study, we utilized stereotactic delivery of adeno-associated virus (AAV)-DUSP4 to overexpress DUSP4 in the dorsal hippocampus of 5×FAD and wildtype (WT) mice, then used mass spectrometry (MS)-based proteomics along with label-free quantification to profile the proteome and phosphoproteome in the hippocampus. We identified patterns of protein expression and phosphorylation that are modulated in 5×FAD mice and examined the sex-specific impact of DUSP4 overexpression on the 5×FAD proteome/phosphoproteome. In 5×FAD mice, a substantial number of proteins were up- or down-regulated in both male and female mice in comparison to age and sex-matched WT mice, many of which are involved in AD-related biological processes, such as the activated immune response or suppression of synaptic activities. Upon DUSP4 overexpression, significantly regulated proteins were found in pathways that were suppressed, such as the immune response, in male 5×FAD mice. In contrast, such a shift was absent in female mice. For the phosphoproteome, we detected an array of phosphorylation sites that are regulated in 5×FAD compared to WT, and are modulated by DUSP4 overexpression in each sex. Interestingly, the changes in 5×FAD- and DUSP4-associated phosphorylation occurred in opposite directions. Strikingly, both the 5×FAD- and DUSP4-associated phosphorylation changes were found for the most part in neurons, and play key roles in neuronal processes and synaptic function. Site-centric pathway analysis revealed that both the 5×FAD- and DUSP4-associated phosphorylation sites were enriched for a number of kinase sets in female, but only a limited number of sets of kinases in male mice. Taken together, our results suggest that male and female 5×FAD mice respond to DUSP4 overexpression via shared and sex-specific molecular mechanisms, which might underly similar reductions in amyloid pathology in both sexes, while learning deficits were reduced in only females with DUSP4 overexpression. Finally, we validated our findings with the sex-specific AD-associated proteomes in human cohorts and further developed DUSP4-centric proteomic network models and signaling maps for each sex.
Language	English
Publishing date	2023-09-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.13.557390
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Proteomic signaling of dual specificity phosphatase 4 (DUSP4) in Alzheimer's disease.

Wang, Erming / Pan, Allen L / Bagchi, Pritha / Ranjaraju, Srikant / Seyfried, Nicholas T / Ehrlich, Michelle E / Salton, Stephen R / Zhang, Bin

Research square

2023

Abstract	DUSP4 is a member of the DUSP (Dual-Specificity Phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimer's disease (AD). In this study, we utilized stereotactic delivery of adeno-associated virus (AAV)-DUSP4 to overexpress DUSP4 in the dorsal hippocampus of 5xFAD and wildtype (WT) mice, then used mass spectrometry (MS)-based proteomics along with label-free quantification to profile the proteome and phosphoproteome in the hippocampus. We identified patterns of protein expression and phosphorylation that are modulated in 5xFAD mice and examined the sex-specific impact of DUSP4 overexpression on the 5xFAD proteome/phosphoproteome. In 5xFAD mice, a substantial number of proteins were up- or down-regulated in both male and female mice in comparison to age and sex-matched WT mice, many of which are involved in AD-related biological processes, such as the activated immune response or suppression of synaptic activities. Upon DUSP4 overexpression, significantly regulated proteins were found in pathways that were suppressed, such as the immune response, in male 5xFAD mice. In contrast, such a shift was absent in female mice. For the phosphoproteome, we detected an array of phosphorylation sites that are regulated in 5xFAD compared to WT, and are modulated by DUSP4 overexpression in each sex. Interestingly, the changes in 5xFAD- and DUSP4-associated phosphorylation occurred in opposite directions. Strikingly, both the 5xFAD- and DUSP4-associated phosphorylation changes were found for the most part in neurons, and play key roles in neuronal processes and synaptic function. Site-centric pathway analysis revealed that both the 5xFAD- and DUSP4-associated phosphorylation sites were enriched for a number of kinase sets in female, but only a limited number of sets of kinases in male mice. Taken together, our results suggest that male and female 5xFAD mice respond to DUSP4 overexpression via shared and sex-specific molecular mechanisms, which might underly similar reductions in amyloid pathology in both sexes, while learning deficits were reduced in only females with DUSP4 overexpression. Finally, we validated our findings with the sex-specific AD-associated proteomes in human cohorts and further developed DUSP4-centric proteomic network models and signaling maps for each sex.
Language	English
Publishing date	2023-10-19
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3453503/v1
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Article ; Online: Epigallocatechin Gallate Mitigates the Methamphetamine-Induced Striatal Dopamine Terminal Toxicity by Preventing Oxidative Stress in the Mouse Brain.

Pan, Allen L / Hasalliu, Ermal / Hasalliu, Manjola / Angulo, Jesus A

Neurotoxicity research

2020 Volume 37, Issue 4, Page(s) 883–892

Abstract: Methamphetamine (METH) is a popular psychostimulant due to its long-lasting effects and inexpensive production. METH intoxication is known to increase oxidative stress leading to neuronal damage. Thus, preventing the METH-induced oxidative stress can ... ...

Abstract	Methamphetamine (METH) is a popular psychostimulant due to its long-lasting effects and inexpensive production. METH intoxication is known to increase oxidative stress leading to neuronal damage. Thus, preventing the METH-induced oxidative stress can potentially mitigate neuronal damage. Previously, our laboratory found that epigallocatechin gallate (EGCG), a strong antioxidant found in green tea, can protect against the METH-induced apoptosis and dopamine terminal toxicity in the striatum of mice. In the present study, we evaluated the anti-oxidative properties of EGCG on the METH-induced oxidative stress using CD-1 mice. First, we demonstrated that mice pretreated with EGCG 30 min prior to the METH injection (30 mg/kg, ip) showed protection against the striatal METH-induced reduction of tyrosine hydroxylase without mitigating hyperthermia. In addition, injecting a single high dose of METH caused the reduction of striatal glutathione peroxidase activity at 24 h after the METH injection. Interestingly, pretreatment with EGCG 30 min prior to the METH injection prevented the METH-induced reduction of glutathione peroxidase activity. Moreover, we utilized Western blots to quantify the glutathione peroxidase 4 protein level in the striatum. The results showed that METH decreased striatal glutathione peroxidase 4 protein level, and the reduction was prevented by EGCG pretreatment. Finally, we observed that the METH-induced increase of striatal catalase and copper/zinc superoxide dismutase protein levels were also attenuated by pretreatment with EGCG. Taken together, our data indicate that EGCG is an effective agent that can be used to mitigate the METH-induced striatal toxicity in the mouse brain.
MeSH term(s)	Animals ; Antioxidants/pharmacology ; Catechin/analogs & derivatives ; Catechin/pharmacology ; Central Nervous System Stimulants/toxicity ; Corpus Striatum/drug effects ; Corpus Striatum/metabolism ; Corpus Striatum/pathology ; Dopamine/metabolism ; Male ; Methamphetamine/toxicity ; Mice ; Oxidative Stress/drug effects ; Oxidative Stress/physiology
Chemical Substances	Antioxidants ; Central Nervous System Stimulants ; Methamphetamine (44RAL3456C) ; Catechin (8R1V1STN48) ; epigallocatechin gallate (BQM438CTEL) ; Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2020-02-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2036826-4
ISSN	1476-3524 ; 1029-8428
ISSN (online)	1476-3524
ISSN	1029-8428
DOI	10.1007/s12640-020-00177-1
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Article: Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice.

Pan, Allen L / Audrain, Mickael / Sakakibara, Emmy / Joshi, Rajeev / Zhu, Xiaodong / Wang, Qian / Wang, Minghui / Beckmann, Noam D / Schadt, Eric E / Gandy, Sam / Zhang, Bin / Ehrlich, Michelle E / Salton, Stephen R

bioRxiv : the preprint server for biology

2023

Abstract: Background: Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal network that regulates late-onset Alzheimer's disease. Importantly, decreased DUSP6 levels are correlated with an increased clinical ... ...

Abstract	Background: Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal network that regulates late-onset Alzheimer's disease. Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model. Methods: AAV5-DUSP6 or AAV5-GFP (control) were stereotactically injected into the dorsal hippocampus (dHc) of female and male 5xFAD or wild type mice to overexpress DUSP6 or GFP. Spatial learning memory of these mice was assessed in the Barnes maze, after which hippocampal tissues were isolated for downstream analysis. Results: Barnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß Conclusions: In summary, our data indicate that DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD.
Language	English
Publishing date	2023-08-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.24.554335
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Article ; Online: Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females.

Cells

2022 Volume 11, Issue 23

Abstract: Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer's disease converged ... ...

Abstract	Recent multiscale network analyses of banked brains from subjects who died of late-onset sporadic Alzheimer's disease converged on
MeSH term(s)	Animals ; Female ; Male ; Mice ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Hippocampus/metabolism ; Protein Tyrosine Phosphatases/genetics ; Learning
Chemical Substances	Amyloid beta-Peptides ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; MKP2 protein, mouse (EC 3.1.3.48) ; Protein Tyrosine Phosphatases (EC 3.1.3.48)
Language	English
Publishing date	2022-12-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11233880
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Prostaglandin D2/J2 signaling pathway in a rat model of neuroinflammation displaying progressive parkinsonian-like pathology: potential novel therapeutic targets.

Corwin, Chuhyon / Nikolopoulou, Anastasia / Pan, Allen L / Nunez-Santos, Mariela / Vallabhajosula, Shankar / Serrano, Peter / Babich, John / Figueiredo-Pereira, Maria E

Journal of neuroinflammation

2018 Volume 15, Issue 1, Page(s) 272

Abstract: Background: Prostaglandins are products of the cyclooxygenase pathway, which is implicated in Parkinson's disease (PD). Limited knowledge is available on mechanisms by which prostaglandins contribute to PD neurodegeneration. To address this gap, we ... ...

Abstract	Background: Prostaglandins are products of the cyclooxygenase pathway, which is implicated in Parkinson's disease (PD). Limited knowledge is available on mechanisms by which prostaglandins contribute to PD neurodegeneration. To address this gap, we focused on the prostaglandin PGD2/J2 signaling pathway, because PGD2 is the most abundant prostaglandin in the brain, and the one that increases the most under pathological conditions. Moreover, PGJ2 is spontaneously derived from PGD2. Methods: In this study, we determined in rats the impact of unilateral nigral PGJ2-microinfusions on COX-2, lipocalin-type PGD2 synthase (L-PGDS), PGD2/J2 receptor 2 (DP2), and 15 hydroxyprostaglandin dehydrogenase (15-PGDH). Nigral dopaminergic (DA) and microglial distribution and expression levels of these key factors of the prostaglandin D2/J2 pathway were evaluated by immunohistochemistry. PGJ2-induced motor deficits were assessed with the cylinder test. We also determined whether oral treatment with ibuprofen improved the PD-like pathology induced by PGJ2. Results: PGJ2 treatment induced progressive PD-like pathology in the rats. Concomitant with DA neuronal loss in the substantia nigra pars compacta (SNpc), PGJ2-treated rats exhibited microglia and astrocyte activation and motor deficits. In DA neurons, COX-2, L-PGDS, and 15-PGDH levels increased significantly in PGJ2-treated rats compared to controls, while DP2 receptor levels were unchanged. In microglia, DP2 receptors were basically non-detectable, while COX-2 and L-PGDS levels increased upon PGJ2-treatment, and 15-PGDH remained unchanged. 15-PGDH was also detected in oligodendrocytes. Notably, ibuprofen prevented most PGJ2-induced PD-like pathology. Conclusions: The PGJ2-induced rat model develops progressive PD pathology, which is a hard-to-mimic aspect of this disorder. Moreover, prevention of most PGJ2-induced PD-like pathology with ibuprofen suggests a positive feedback mechanism between PGJ2 and COX-2 that could lead to chronic neuroinflammation. Notably, this is the first study that analyzes the nigral dopaminergic and microglial distribution and levels of factors of the PGD2/J2 signaling pathway in rodents. Our findings support the notions that upregulation of COX-2 and L-PGDS may be important in the PGJ2 evoked PD-like pathology, and that neuronal DP2 receptor antagonists and L-PGDS inhibitors may be novel pharmacotherapeutics to relieve neuroinflammation-mediated neurodegeneration in PD, circumventing the adverse side effects of cyclooxygenase inhibitors.
MeSH term(s)	Animals ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Antineoplastic Agents/toxicity ; Disease Models, Animal ; Encephalitis/chemically induced ; Encephalitis/complications ; Encephalitis/drug therapy ; Encephalitis/metabolism ; Exploratory Behavior/drug effects ; Exploratory Behavior/physiology ; Functional Laterality/drug effects ; Ibuprofen/therapeutic use ; Male ; Microglia/drug effects ; Neurons/drug effects ; Neurons/metabolism ; Parkinsonian Disorders/etiology ; Parkinsonian Disorders/pathology ; Phosphopyruvate Hydratase/metabolism ; Prostaglandin D2/analogs & derivatives ; Prostaglandin D2/metabolism ; Prostaglandin D2/toxicity ; Psychomotor Performance/drug effects ; Rats ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Substantia Nigra/drug effects ; Substantia Nigra/metabolism ; Substantia Nigra/pathology ; Tyrosine 3-Monooxygenase/metabolism
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; Antineoplastic Agents ; 9-deoxy-delta-9-prostaglandin D2 (60203-57-8) ; Tyrosine 3-Monooxygenase (EC 1.14.16.2) ; Phosphopyruvate Hydratase (EC 4.2.1.11) ; Prostaglandin D2 (RXY07S6CZ2) ; Ibuprofen (WK2XYI10QM)
Language	English
Publishing date	2018-09-20
Publishing country	England
Document type	Journal Article
ISSN	1742-2094
ISSN (online)	1742-2094
DOI	10.1186/s12974-018-1305-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Proteomic Signaling of Dual-Specificity Phosphatase 4 (DUSP4) in Alzheimer's Disease.

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Article: Proteomic signaling of dual specificity phosphatase 4 (DUSP4) in Alzheimer's disease.

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Inter-library loan at ZB MED

Article: Proteomic signaling of dual specificity phosphatase 4 (DUSP4) in Alzheimer's disease.

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Inter-library loan at ZB MED

Article ; Online: Epigallocatechin Gallate Mitigates the Methamphetamine-Induced Striatal Dopamine Terminal Toxicity by Preventing Oxidative Stress in the Mouse Brain.

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Article: Dual-specificity protein phosphatase 6 (DUSP6) overexpression reduces amyloid load and improves memory deficits in male 5xFAD mice.

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Article ; Online: Dual-Specificity Protein Phosphatase 4 (DUSP4) Overexpression Improves Learning Behavior Selectively in Female 5xFAD Mice, and Reduces β-Amyloid Load in Males and Females.

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Article ; Online: Prostaglandin D2/J2 signaling pathway in a rat model of neuroinflammation displaying progressive parkinsonian-like pathology: potential novel therapeutic targets.

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Inter-library loan at ZB MED