COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

Wang, Hongjie; Dey, Debadeepta; Carrera, Iván; Minond, Dmitriy; Bianchi, Elisabetta; Xu, Shaohua; Lakshmana, Madepalli K.

doi:10.1074/jbc.m113.476689

Cited by 20 publications

(27 citation statements)

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“…We showed previously that COPS5 binds LRP, BACE1, APP, and RanBP9 in cell lines as well as in mouse brains, leading to a robust increase in the secretion of A␤ (27). The observation by others that both RanBP9 and COPS5 are present in the same subcellular fractions of the multiprotein complex (28) strengthened our conclusion that COPS5 is a novel member of the FIGURE 6.…”

Section: Volume 290 • Number 14 • April 3 2015supporting

confidence: 68%

“…This implies that COPS5 increases A␤ generation and amyloid plaque burden by increasing RanBP9 protein levels through its stabilization. In N2A cells also, overexpression of COPS5 led to more than a 3-fold increase in RanBP9 protein levels (27). This is direct evidence that COPS5 acts through RanBP9 in increasing the amyloidogenic processing of APP.…”

Section: Volume 290 • Number 14 • April 3 2015supporting

confidence: 49%

“…COPS5 Overexpression Increases RanBP9, CTF-␤, and sAPP␤ and Decreases CTF-␣ and sAPP␣ Levels-COPS5 overexpression in NT2 cells robustly increased RanBP9 protein by inhibiting its degradation, thereby stabilizing the protein levels (27). Therefore, we quantified RanBP9 protein levels to see whether the same is true in vivo.…”

Section: Cops5 Overexpression Increases A␤ Levels and Amyloid Plaque mentioning

confidence: 99%

“…Brain-Because COPS5 overexpression in cell cultures led to a robust increase in A␤ levels (27), we were first interested to confirm whether such an effect is also seen in vivo in the mouse brain. A␤ was extracted from both CHAPSO-soluble and formic acid-soluble fractions from the brains of AP⌬E9/COPS5 and AP⌬E9 mice at both 6 and 12 months of age.…”

Section: Cops5 Overexpression Increases A␤ Levels and Amyloid Plaque mentioning

confidence: 99%

“…In fact, we demonstrated previously that RanBP9 is an important component of a multiprotein complex involving LRP, BACE1, and APP that robustly increased A␤ levels (19,20) and substantially reduced synaptic proteins (21)(22)(23)(24)(25) because of reduced dendritic intersections and spine density (26), consequently leading to severe deficits in learning and memory performance in AP⌬E9 mice overexpressing RanBP9 (23,25). We also recently identified COP9 constitutive photomorphogenic homolog subunit 5 (COPS5, Jab1) as a bona fide binding partner of RanBP9 (27). To understand the role of COPS5 in vivo in the amyloidogenic processing of APP, we successfully generated and characterized transgenic mice overexpressing FLAG-COPS5.…”

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COPS5 Protein Overexpression Increases Amyloid Plaque Burden, Decreases Spinophilin-immunoreactive Puncta, and Exacerbates Learning and Memory Deficits in the Mouse Brain

Wang

Carrera

et al. 2015

Journal of Biological Chemistry

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Background: Alzheimer disease (AD) is characterized by increased generation of amyloid ␤ (A␤) peptide in the brain. Results: COPS5 overexpression increases A␤, amyloid plaque burden, and learning deficits in a mouse model of AD. Conclusion: As a RanBP9-interacting protein, COPS5 also plays a pivotal role in A␤ generation in vivo. Significance: Targeting the COPS5-RanBP9 pathway may be an effective therapeutic approach for AD.

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Section: Volume 290 • Number 14 • April 3 2015supporting

confidence: 68%

Section: Volume 290 • Number 14 • April 3 2015supporting

confidence: 49%

Section: Cops5 Overexpression Increases A␤ Levels and Amyloid Plaque mentioning

confidence: 99%

Section: Cops5 Overexpression Increases A␤ Levels and Amyloid Plaque mentioning

confidence: 99%

mentioning

confidence: 99%

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COPS5 Protein Overexpression Increases Amyloid Plaque Burden, Decreases Spinophilin-immunoreactive Puncta, and Exacerbates Learning and Memory Deficits in the Mouse Brain

Wang

Carrera

et al. 2015

Journal of Biological Chemistry

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Detection of early proteomic alterations in 5xFAD Alzheimer's disease neonatal mouse model via MALDI‐MSI

Uras

Karayel-Basar

Sahin

et al. 2023

Alzheimer's & Dementia

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Alzheimer's disease (AD) is a debilitating neurodegenerative disorder, characterized by memory deficit and dementia. AD is considered a multifactorial disorder where multiple processes like amyloid‐beta and tau accumulation, axonal degeneration, synaptic plasticity, and autophagic processes plays an important role. In this study, the spatial proteomic differences in the neonatal 5xFAD brain tissue were investigated using MALDI‐MSI coupled to LC‐MS/MS, and the statistically significantly altered proteins were associated with AD. Thirty‐five differentially expressed proteins (DEPs) between the brain tissues of neonatal 5xFAD and their littermate mice were detected via MALDI‐MSI technique. Among the 35 proteins identified, 26 of them were directly associated with AD. Our results indicated a remarkable resemblance in the protein expression profiles of neonatal 5xFAD brain when compared to AD patient specimens or AD mouse models. These findings showed that the molecular alterations in the AD brain existed even at birth and that some proteins are neurodegenerative presages in neonatal AD brain.Highlights Spatial proteomic alterations in the 5xFAD mouse brain compared to the littermate. 26 out of 35 differentially expressed proteins associated with Alzheimer's disease (AD). Molecular alterations and neurodegenerative presages in neonatal AD brain. Alterations in the synaptic function an early and common neurobiological thread.

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Identification of binding partners that facilitate membrane‐type 5 matrix metalloproteinase (MT5‐MMP) processing of amyloid precursor protein

Wang,

Lakshmana,

Fields

2024

Journal Cellular Physiology

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One of the pathological hallmarks of Alzheimer's disease (AD) is the presence of extracellular deposits of amyloid beta (Aβ) peptide. In addition to Aβ as the core component of the amyloid plaque, the amyloid precursor protein (APP) processing fragment Aβ was also found accumulated around the plaque. The APPη pathway, mainly mediated by membrane‐type 5 matrix metalloproteinase (MT5‐MMP), represents an important factor in AD pathogenesis. The proamyloidogenic features of MT5‐MMP could result from interactions with APP when trafficking between organelles, so determination of the location within the cell of APPη cleavage and interacting proteins of MT5‐MMP affecting this process will be of priority in understanding the role of MT5‐MMP in AD. In the present study, MT5‐MMP was found to be located in the nucleus, cytosol, and cytosolic subcellular granules of CHO cells that stably expressed wild‐type human APP751. MT5‐MMP fusion proteins were constructed that could localize enzyme production in the Golgi apparatus, endosome, ER, mitochondria, or plasma membrane. The fusion proteins significantly increased sAPPη when directed to the endosome, Golgi apparatus, plasma membrane, or mitochondria. Since the C‐terminal region of MT5‐MMP is responsible for its intracellular location and trafficking, this domain was used as the bait in a yeast two‐hybrid screen to identify MT5‐MMP protein partners in a human brain cDNA library. Identified binding partners included N4BP2L1, TMX3, EIG121, bridging Integrator 1 (BIN1), RUFY4, HTRA1, and TMEM199. The binding of N4BP2L1, EIG121, BIN1, or TMX3 to MT5‐MMP resulted in the most significant increase in sAPPη production. Thus, the action of MT5‐MMP on APP occurs in multiple locations within the cell and is facilitated by site‐specific binding partners.

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COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

Cited by 20 publications

References 43 publications

COPS5 Protein Overexpression Increases Amyloid Plaque Burden, Decreases Spinophilin-immunoreactive Puncta, and Exacerbates Learning and Memory Deficits in the Mouse Brain

COPS5 Protein Overexpression Increases Amyloid Plaque Burden, Decreases Spinophilin-immunoreactive Puncta, and Exacerbates Learning and Memory Deficits in the Mouse Brain

Detection of early proteomic alterations in 5xFAD Alzheimer's disease neonatal mouse model via MALDI‐MSI

Identification of binding partners that facilitate membrane‐type 5 matrix metalloproteinase (MT5‐MMP) processing of amyloid precursor protein

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