Probing the Mint2 Protein–Protein Interaction Network Relevant to the Pathophysiology of Alzheimer's Disease

Jensen, Torben Pilegaard; Albertsen, Louise; Bartling, Christian R. O.; Haugaard‐Kedström, Linda M.; Strømgaard, Kristian

doi:10.1002/cbic.201800004

Cited by 8 publications

(7 citation statements)

References 30 publications

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“…[310] The PTB domain of Mint proteins interacts with APP C-terminal region peptide motif, YENPTY, while the first PDZ domain of Mint interacts with presenilin-1, a constituent of the γ -secretase complex. [317] Another protein potentially relevant in the treatment of AD is HtrA1. Further evidence for this mechanism comes from the reduction in the Aβ levels in mice brain after the genetic replacement of APP gene (APP) with a variant lacking the last 15 amino acids, including the YENPTY sequence.…”

Section: Potential Future Pdz Domain Protein Drug Targetsmentioning

confidence: 99%

“…Further evidence for this mechanism comes from the reduction in the Aβ levels in mice brain after the genetic replacement of APP gene ( APP ) with a variant lacking the last 15 amino acids, including the YENPTY sequence . In addition to presenilin and APP, some additional Mint interaction partners have been reported, which are also believed to play a role in the amyloidogenic pathway …”

Section: Potential Future Pdz Domain Protein Drug Targetsmentioning

confidence: 99%

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PDZ Domains as Drug Targets

Christensen

Čalyševa

Fernandes

et al. 2019

Advanced Therapeutics

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Protein-protein interactions within protein networks shape the human interactome, which often is promoted by specialized protein interaction modules, such as the postsynaptic density-95 (PSD-95), discs-large, zona occludens 1 (ZO-1) (PDZ) domains. PDZ domains play a role in several cellular functions, from cell-cell communication and polarization, to regulation of protein transport and protein metabolism. PDZ domain proteins are also crucial in the formation and stability of protein complexes, establishing an important bridge between extracellular stimuli detected by transmembrane receptors and intracellular responses. PDZ domains have been suggested as promising drug targets in several diseases, ranging from neurological and oncological disorders to viral infections. In this review, the authors describe structural and genetic aspects of PDZ-containing proteins and discuss the current status of the development of small-molecule and peptide modulators of PDZ domains. An overview of potential new therapeutic interventions in PDZ-mediated protein networks is also provided.

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Section: Potential Future Pdz Domain Protein Drug Targetsmentioning

confidence: 99%

Section: Potential Future Pdz Domain Protein Drug Targetsmentioning

confidence: 99%

PDZ Domains as Drug Targets

Christensen

Čalyševa

Fernandes

et al. 2019

Advanced Therapeutics

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“…Munc-18 and complexin are part of a family of neuronal vesicular proteins regulating the SNARE complex which is involved in rapid exocytosis and neurotransmitter release at neuronal synapses (Pabst et al, 2002;Sudhof, 2013;Tang et al, 2006). Mechanistically, this complex directly binds to APP causing increased aggregation of Aβ in the brain and indeed, these proteins are physically located in proximity to aggregated Aβ (Chaufty, Sullivan, & Ho, 2012;Jensen, Albertsen, Bartling, Haugaard-Kedstrom, & Stromgaard, 2018). Thus, although alcohol drinking induced differential changes in the PFC and AMY proteome, specific target proteins in each brain region are known to regulate aspects AD pathology.…”

Section: Alcohol-induced Impact On the Neuroproteome And Admentioning

confidence: 99%

Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease

Hoffman

Faccidomo

Kim

et al. 2019

International Review of Neurobiology

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that nondependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, two-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins MAPT (Tau), amyloid beta precursor protein (APP), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, HK1, AK1, PGAM1, CKB), cytoskeletal development (BASP1, CAP1, DPYSL2 [CRMP2], ALDOA, TUBA1A, CFL2, ACTG1), cellular/oxidative stress (HSPA5, HSPA8, ENO1, ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human MAPT, APP, and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wild-type mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol-free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex, medial prefrontal cortex, and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late-stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer’s pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, IRS1, IGF1R, PTEN, ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.

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“…; Jensen et al . ). Identification of the phosphorylation site(s) is important for further understanding of the mechanisms regulating the interaction between X11s and NMDA receptors.…”

Section: Discussionmentioning

confidence: 97%

X11 and X11‐like proteins regulate the level of extrasynaptic glutamate receptors

Motodate

Saito

Sobu

et al. 2018

Journal of Neurochemistry

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X11/Mint 1 and X11-like (X11L)/Mint 2 are neuronal adaptor protein to regulate trafficking and/or localization of various membrane proteins. By analyzing the localization of neuronal membrane proteins in X11-, X11L-, and X11/X11L doubly deficient mice with membrane fractionation procedures, we found that deficient of X11 and X11L decreased the level of glutamate receptors in non-PSD fraction. This finding suggests that X11 and X11L regulate the glutamate receptor micro-localization to the extrasynaptic region. In vitro coimmunoprecipitation studies of NMDA receptors lacking various cytoplasmic regions with X11 and X11L proteins harboring domain deletion suggest that extrasynaptic localization of NMDA receptor may be as a result of the multiple interactions of the receptor subunits with X11 and X11L regulated by protein phosphorylation, while that of a-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor subunits is not dependent on the binding with X11 and X11L proteins. Because the loss of X11 and X11L tends to impair the exocytosis, but not endocytosis, of glutamate receptors, NMDA receptors are likely to be supplied to the extrasynaptic plasma membrane with a way distinct from the mechanism regulating the localization of NMDA receptors into synaptic membrane region. Reduced localization of NMDA receptor into the extrasynaptic region increased slightly the phosphorylation level of cAMP responsible element binding protein in brain of X11/X11L doubly deficient mice compare to wild-type mice, suggesting a possible role of X11 and X11L in the regulation of signal transduction pathway through extrasynaptic glutamate receptors. Abbreviations used: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ApoER2, apolipoprotein E receptor 2; APP, amyloid bprotein precursor; CREB, cAMP responsible element binding protein; NMDA, N-methyl-D-aspartate; PDZ, postsynaptic density (PSD)95/ discs-large/zona occludens-1; PTB, phosphotyrosine-binding; RRID, research resource identifier; X11L, X11-like. 480

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Probing the Mint2 Protein–Protein Interaction Network Relevant to the Pathophysiology of Alzheimer's Disease

Cited by 8 publications

References 30 publications

PDZ Domains as Drug Targets

PDZ Domains as Drug Targets

Alcohol drinking exacerbates neural and behavioral pathology in the 3xTg-AD mouse model of Alzheimer's disease

X11 and X11‐like proteins regulate the level of extrasynaptic glutamate receptors

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