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FMRP mediates mGluR5-dependent translation of amyloid precursor protein.

Westmark CJ, Malter JS - PLoS Biol. (2007)

Bottom Line: Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Abeta) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission.APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment.Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, Wisconsin, United States of America. westmark@facstaff.wisc.edu

ABSTRACT
Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Abeta) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expression is lost in fragile X syndrome. Here we show that FMRP binds to the coding region of APP mRNA at a guanine-rich, G-quartet-like sequence. Stimulation of cortical synaptoneurosomes or primary neuronal cells with the metabotropic glutamate receptor agonist DHPG increased APP translation in wild-type but not fmr-1 knockout samples. APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment. Soluble Abeta40 or Abeta42 levels were significantly higher in multiple strains of fmr-1 knockout mice compared to wild-type controls. Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome.

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mGluR Activation Increases APP Translation in SNs(A) Immunoprecipitated, 35S-labeled APP (120-kDa band) from WT (15 min) and KO and WT (60 min) SNs analyzed by SDS-PAGE and (B) plotted as a percentage of APP synthesis; n = 3 repetitions. Asterisk indicates significant differences, with p = 0.008 between ±DHPG samples at 15 min and p = 0.016 between control at 15 min and DHPG at 60 min. For the control samples at 15 and 60 min, p = 0.056, and for the samples with or without DHPG at 60 min, p = 0.05. (C) Immunoprecipitated, 35S-labeled APP (120-kDa band) from WT SNs treated with DHPG, anisomycin, and MPEP, analyzed by SDS-PAGE, and (D) plotted as a percentage of APP synthesis; n = 3 repetitions (DHPG), n = 4 (anisomycin + DHPG and anisomycin), and n = 5 (MPEP + DHPG and MPEP).
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pbio-0050052-g003: mGluR Activation Increases APP Translation in SNs(A) Immunoprecipitated, 35S-labeled APP (120-kDa band) from WT (15 min) and KO and WT (60 min) SNs analyzed by SDS-PAGE and (B) plotted as a percentage of APP synthesis; n = 3 repetitions. Asterisk indicates significant differences, with p = 0.008 between ±DHPG samples at 15 min and p = 0.016 between control at 15 min and DHPG at 60 min. For the control samples at 15 and 60 min, p = 0.056, and for the samples with or without DHPG at 60 min, p = 0.05. (C) Immunoprecipitated, 35S-labeled APP (120-kDa band) from WT SNs treated with DHPG, anisomycin, and MPEP, analyzed by SDS-PAGE, and (D) plotted as a percentage of APP synthesis; n = 3 repetitions (DHPG), n = 4 (anisomycin + DHPG and anisomycin), and n = 5 (MPEP + DHPG and MPEP).

Mentions: To assess de novo synthesis, 35S-labeled WT or KO SNs were immunoprecipitated with anti-APP. After 15 min of incubation, untreated WT SNs translated modest amounts of APP, which rapidly increased by 2.7-fold with DHPG treatment. After 1 hr, APP remained elevated in stimulated SNs over the control, but the difference was less (1.6-fold) than at 15 min, suggesting more persistent translation in the unstimulated controls, slowing of new synthesis after stimulation, and/or compensatory protein turnover in the DHPG-treated samples (Figure 3A and 3B). In KO SNs, APP synthesis was less than in WT SNs and showed a minimal response to DHPG. The translational inhibitor anisomycin blocked DHPG-mediated synthesis of APP, as did the specific mGluR5 inhibitor MPEP (Figure 3C and 3D).


FMRP mediates mGluR5-dependent translation of amyloid precursor protein.

Westmark CJ, Malter JS - PLoS Biol. (2007)

mGluR Activation Increases APP Translation in SNs(A) Immunoprecipitated, 35S-labeled APP (120-kDa band) from WT (15 min) and KO and WT (60 min) SNs analyzed by SDS-PAGE and (B) plotted as a percentage of APP synthesis; n = 3 repetitions. Asterisk indicates significant differences, with p = 0.008 between ±DHPG samples at 15 min and p = 0.016 between control at 15 min and DHPG at 60 min. For the control samples at 15 and 60 min, p = 0.056, and for the samples with or without DHPG at 60 min, p = 0.05. (C) Immunoprecipitated, 35S-labeled APP (120-kDa band) from WT SNs treated with DHPG, anisomycin, and MPEP, analyzed by SDS-PAGE, and (D) plotted as a percentage of APP synthesis; n = 3 repetitions (DHPG), n = 4 (anisomycin + DHPG and anisomycin), and n = 5 (MPEP + DHPG and MPEP).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC1808499&req=5

pbio-0050052-g003: mGluR Activation Increases APP Translation in SNs(A) Immunoprecipitated, 35S-labeled APP (120-kDa band) from WT (15 min) and KO and WT (60 min) SNs analyzed by SDS-PAGE and (B) plotted as a percentage of APP synthesis; n = 3 repetitions. Asterisk indicates significant differences, with p = 0.008 between ±DHPG samples at 15 min and p = 0.016 between control at 15 min and DHPG at 60 min. For the control samples at 15 and 60 min, p = 0.056, and for the samples with or without DHPG at 60 min, p = 0.05. (C) Immunoprecipitated, 35S-labeled APP (120-kDa band) from WT SNs treated with DHPG, anisomycin, and MPEP, analyzed by SDS-PAGE, and (D) plotted as a percentage of APP synthesis; n = 3 repetitions (DHPG), n = 4 (anisomycin + DHPG and anisomycin), and n = 5 (MPEP + DHPG and MPEP).
Mentions: To assess de novo synthesis, 35S-labeled WT or KO SNs were immunoprecipitated with anti-APP. After 15 min of incubation, untreated WT SNs translated modest amounts of APP, which rapidly increased by 2.7-fold with DHPG treatment. After 1 hr, APP remained elevated in stimulated SNs over the control, but the difference was less (1.6-fold) than at 15 min, suggesting more persistent translation in the unstimulated controls, slowing of new synthesis after stimulation, and/or compensatory protein turnover in the DHPG-treated samples (Figure 3A and 3B). In KO SNs, APP synthesis was less than in WT SNs and showed a minimal response to DHPG. The translational inhibitor anisomycin blocked DHPG-mediated synthesis of APP, as did the specific mGluR5 inhibitor MPEP (Figure 3C and 3D).

Bottom Line: Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Abeta) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission.APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment.Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, Wisconsin, United States of America. westmark@facstaff.wisc.edu

ABSTRACT
Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Abeta) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expression is lost in fragile X syndrome. Here we show that FMRP binds to the coding region of APP mRNA at a guanine-rich, G-quartet-like sequence. Stimulation of cortical synaptoneurosomes or primary neuronal cells with the metabotropic glutamate receptor agonist DHPG increased APP translation in wild-type but not fmr-1 knockout samples. APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment. Soluble Abeta40 or Abeta42 levels were significantly higher in multiple strains of fmr-1 knockout mice compared to wild-type controls. Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome.

Show MeSH
Related in: MedlinePlus