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Fragile X mental retardation protein: from autism to neurodegenerative disease.

Wang H - Front Cell Neurosci (2015)

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, University of Toronto Toronto, ON, Canada.

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Fragile X mental retardation protein (FMRP) is a RNA binding protein, the absence of which due to silencing of the FMR1 gene causes fragile X syndrome, an X-linked neurodevelopmental disorder (Bassell and Warren, ; Bhakar et al., ; Santoro et al., )... More and more potential FMRP mRNA targets and interacting proteins have been identified in the mammalian brain, supporting the critical roles of FMRP in neurodevelopment, synaptic plasticity and other neurological disorders apart from fragile X syndrome (Wang et al.,, ; Pasciuto and Bagni, ; Suhl et al., )... Fragile X syndrome, the most common monogenic cause of autism spectrum disorders (ASDs), has been leading the way for better understanding of autism and other neurodevelopmental disorders (Belmonte and Bourgeron, ; Bhakar et al., ; Banerjee et al., ; Cook et al., )... Those receptors include, but are not limited to, NMDARs, mGluR5, AMPARs, cellular prion protein (PrP), PSD-95, and EphB2 (Lacor et al., ; Lauren et al., ; Cisse et al., ; Larson and Lesne, ; Mucke and Selkoe, ; Um et al., ; Tu et al., )... In fact, some of Aβ receptors (NMDARs, mGluR5, and PSD-95) and their associated scaffolding proteins and adhesion molecules such as SAPAP, Shank, Homer, and SynGAP1, are those whose mRNAs are FMRP targets (Darnell and Klann, ; Santini and Klann, ), suggesting that FMRP might be involved in initiating toxic effects of Aβ oligomers through regulating Aβ receptors (Figure 1A)... Thus, in addition to the established role in fragile X syndrome and autism, FMRP likely contributes directly to AD pathogenesis through mGluR5 dependent APP production... As discussed above, a number of signaling pathways, including PI3K-Akt-mTORC1, MEK-ERK and PAK1 pathways, have been found to be involved in the neurodegenerative progression of AD... In addition, the FMRP targeted Aβ oligomer receptors including mGluR5 and NMDARs could be ideal therapeutic targets for AD (Figure 1A)... Particularly, pharmacological inhibition or genetic deletion of mGluR5 was recently found to rescue learning deficits, or reduce Aβ oligomers and plaques in AD mice (Um et al., ; Hamilton et al., )... The relevant kinases and phosphatases could be the FMRP targets such as GSK3β, ERK, S6K1, PP2A, PTEN, and STEP (Figure 1A)... Although the tau based treatments are encouraging, additional work are undoubtedly needed to optimize each treatment for further development of safe and effective therapies... FMRP thus, acts as a molecular link between ASDs and AD through the common signaling pathways among the diseases... Developing novel therapies directed at FMRP targets may benefit both neurodevelopmental and neurodegenerative disorders... It is now known that FMRP controls signaling pathways that could be associated with both neurodevelopmental and neurodegenerative disorders.

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Related in: MedlinePlus

Potential roles of FMRP in the pathogenesis of AD. (A) FMRP might be involved in oligomeric Aβ induced neurotoxicity. At pathological concentrations, Aβ oligomers may interact with multiple neuronal synaptic receptors such as mGluR5-PrPC, NMDARs, AMPARs, and EphB2, triggering a series of toxic synaptic events which may involve FMRP and eventually lead to synaptic dysfunction and neuronal loss. These events include: Aberrant activation of PI3K-Akt-mTORC1 and MEK-ERK signaling pathways linked to cap-dependent translation result in altered synthesis of synaptic proteins; Oligomeric Aβ exposure disrupts the balance between tau kinase (GSK3β, CaMKII, Akt, Fyn, and ERK1/2) and phosphatase (PP2A, STEP, and PTEN) activities, inducing tau hyperphosphorylation and aggregation; Stimulating EphB2-Rac1/PAK1 signaling by Aβ oligomers induces cofilin phosphorylation and actin depolymerization, leading to actin network disorganization; Binding of Aβ oligomers to PrPC-mGluR5 activates Fyn kinase which phosphorylates not only tau, but also NR2B subunit of NMDARs, enhancing NMDAR activity and causing excitotoxicity; STEP is also activated, inactivates Fyn, and dephosphorylates AMPARs and NMDARs, resulting in endocytosis of glutamate receptors, a cellular process involves Arc, PSD-95, SAPAP, and other synaptic proteins. Purple proteins are those whose mRNAs are FMRP targets (Darnell and Klann, 2013; Pasciuto and Bagni, 2014b; Santini and Klann, 2014); the blue ones are the interacting proteins of FMRP (Pasciuto and Bagni, 2014a). Proteins with red lines around them indicate those that have been successfully manipulated either pharmacologically or genetically to reverse molecular, cellular and/or behavioral phenotypes in animal models of AD (Zhang et al., 2010; Malinow, 2012; Caccamo et al., 2014; Feld et al., 2014; Hamilton et al., 2014; Llorens-Martin et al., 2014) as well as ASDs (Goebel-Goody et al., 2012; Guo et al., 2012; Won et al., 2012; Darnell and Klann, 2013; Osterweil et al., 2013; Wang and Doering, 2013; Wang, 2014). Proteins with black lines around them are the ones that have been reported to be potential targets for AD therapy (Griffin et al., 2005; Lafay-Chebassier et al., 2005; Ma et al., 2008; Cisse et al., 2011; Moriguchi, 2011; Chang et al., 2012; Gross and Bassell, 2014; Nygaard et al., 2014; Sontag and Sontag, 2014). (B) FMRP in APP synthesis. Aβ oligomers stimulate dendritic APP synthesis through PrPC-mGluR5 mediated protein translation dependent pathway, providing template for secretase cleavage to produce Aβ and other metabolites. A positive feedback may exist whereby production of APP results in increased substrate for amyloidogenic processing and release of Aβ, which then acitivates mGluR5 to further stimulate APP translation. In this process, FMRP competes with the other RNA binding protein hnRNP C to modulate APP translation. FMRP is a repressor of APP translation, whereas hnRNP C acts as an enhancer. The rate of APP synthesis is directly influenced by the relative association of each RNA binding protein (Lee et al., 2010). In signaling pathways, arrows indicate positive (green) or inhibitory (red) consequence on downstream components, but they do not necessarily represent direct interactions.
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Figure 1: Potential roles of FMRP in the pathogenesis of AD. (A) FMRP might be involved in oligomeric Aβ induced neurotoxicity. At pathological concentrations, Aβ oligomers may interact with multiple neuronal synaptic receptors such as mGluR5-PrPC, NMDARs, AMPARs, and EphB2, triggering a series of toxic synaptic events which may involve FMRP and eventually lead to synaptic dysfunction and neuronal loss. These events include: Aberrant activation of PI3K-Akt-mTORC1 and MEK-ERK signaling pathways linked to cap-dependent translation result in altered synthesis of synaptic proteins; Oligomeric Aβ exposure disrupts the balance between tau kinase (GSK3β, CaMKII, Akt, Fyn, and ERK1/2) and phosphatase (PP2A, STEP, and PTEN) activities, inducing tau hyperphosphorylation and aggregation; Stimulating EphB2-Rac1/PAK1 signaling by Aβ oligomers induces cofilin phosphorylation and actin depolymerization, leading to actin network disorganization; Binding of Aβ oligomers to PrPC-mGluR5 activates Fyn kinase which phosphorylates not only tau, but also NR2B subunit of NMDARs, enhancing NMDAR activity and causing excitotoxicity; STEP is also activated, inactivates Fyn, and dephosphorylates AMPARs and NMDARs, resulting in endocytosis of glutamate receptors, a cellular process involves Arc, PSD-95, SAPAP, and other synaptic proteins. Purple proteins are those whose mRNAs are FMRP targets (Darnell and Klann, 2013; Pasciuto and Bagni, 2014b; Santini and Klann, 2014); the blue ones are the interacting proteins of FMRP (Pasciuto and Bagni, 2014a). Proteins with red lines around them indicate those that have been successfully manipulated either pharmacologically or genetically to reverse molecular, cellular and/or behavioral phenotypes in animal models of AD (Zhang et al., 2010; Malinow, 2012; Caccamo et al., 2014; Feld et al., 2014; Hamilton et al., 2014; Llorens-Martin et al., 2014) as well as ASDs (Goebel-Goody et al., 2012; Guo et al., 2012; Won et al., 2012; Darnell and Klann, 2013; Osterweil et al., 2013; Wang and Doering, 2013; Wang, 2014). Proteins with black lines around them are the ones that have been reported to be potential targets for AD therapy (Griffin et al., 2005; Lafay-Chebassier et al., 2005; Ma et al., 2008; Cisse et al., 2011; Moriguchi, 2011; Chang et al., 2012; Gross and Bassell, 2014; Nygaard et al., 2014; Sontag and Sontag, 2014). (B) FMRP in APP synthesis. Aβ oligomers stimulate dendritic APP synthesis through PrPC-mGluR5 mediated protein translation dependent pathway, providing template for secretase cleavage to produce Aβ and other metabolites. A positive feedback may exist whereby production of APP results in increased substrate for amyloidogenic processing and release of Aβ, which then acitivates mGluR5 to further stimulate APP translation. In this process, FMRP competes with the other RNA binding protein hnRNP C to modulate APP translation. FMRP is a repressor of APP translation, whereas hnRNP C acts as an enhancer. The rate of APP synthesis is directly influenced by the relative association of each RNA binding protein (Lee et al., 2010). In signaling pathways, arrows indicate positive (green) or inhibitory (red) consequence on downstream components, but they do not necessarily represent direct interactions.

Mentions: A growing number of synaptic proteins have been proposed as potential Aβ receptors or coreceptors, which are believed to mediate Aβ induced synaptic dysfunction (Karran et al., 2011; Paula-Lima et al., 2013; Pozueta et al., 2013; Overk and Masliah, 2014). Those receptors include, but are not limited to, NMDARs, mGluR5, AMPARs, cellular prion protein (PrPC), PSD-95, and EphB2 (Lacor et al., 2004; Lauren et al., 2009; Cisse et al., 2011; Larson and Lesne, 2012; Mucke and Selkoe, 2012; Um et al., 2013; Tu et al., 2014). In fact, some of Aβ receptors (NMDARs, mGluR5, and PSD-95) and their associated scaffolding proteins and adhesion molecules such as SAPAP, Shank, Homer, and SynGAP1, are those whose mRNAs are FMRP targets (Darnell and Klann, 2013; Santini and Klann, 2014), suggesting that FMRP might be involved in initiating toxic effects of Aβ oligomers through regulating Aβ receptors (Figure 1A).


Fragile X mental retardation protein: from autism to neurodegenerative disease.

Wang H - Front Cell Neurosci (2015)

Potential roles of FMRP in the pathogenesis of AD. (A) FMRP might be involved in oligomeric Aβ induced neurotoxicity. At pathological concentrations, Aβ oligomers may interact with multiple neuronal synaptic receptors such as mGluR5-PrPC, NMDARs, AMPARs, and EphB2, triggering a series of toxic synaptic events which may involve FMRP and eventually lead to synaptic dysfunction and neuronal loss. These events include: Aberrant activation of PI3K-Akt-mTORC1 and MEK-ERK signaling pathways linked to cap-dependent translation result in altered synthesis of synaptic proteins; Oligomeric Aβ exposure disrupts the balance between tau kinase (GSK3β, CaMKII, Akt, Fyn, and ERK1/2) and phosphatase (PP2A, STEP, and PTEN) activities, inducing tau hyperphosphorylation and aggregation; Stimulating EphB2-Rac1/PAK1 signaling by Aβ oligomers induces cofilin phosphorylation and actin depolymerization, leading to actin network disorganization; Binding of Aβ oligomers to PrPC-mGluR5 activates Fyn kinase which phosphorylates not only tau, but also NR2B subunit of NMDARs, enhancing NMDAR activity and causing excitotoxicity; STEP is also activated, inactivates Fyn, and dephosphorylates AMPARs and NMDARs, resulting in endocytosis of glutamate receptors, a cellular process involves Arc, PSD-95, SAPAP, and other synaptic proteins. Purple proteins are those whose mRNAs are FMRP targets (Darnell and Klann, 2013; Pasciuto and Bagni, 2014b; Santini and Klann, 2014); the blue ones are the interacting proteins of FMRP (Pasciuto and Bagni, 2014a). Proteins with red lines around them indicate those that have been successfully manipulated either pharmacologically or genetically to reverse molecular, cellular and/or behavioral phenotypes in animal models of AD (Zhang et al., 2010; Malinow, 2012; Caccamo et al., 2014; Feld et al., 2014; Hamilton et al., 2014; Llorens-Martin et al., 2014) as well as ASDs (Goebel-Goody et al., 2012; Guo et al., 2012; Won et al., 2012; Darnell and Klann, 2013; Osterweil et al., 2013; Wang and Doering, 2013; Wang, 2014). Proteins with black lines around them are the ones that have been reported to be potential targets for AD therapy (Griffin et al., 2005; Lafay-Chebassier et al., 2005; Ma et al., 2008; Cisse et al., 2011; Moriguchi, 2011; Chang et al., 2012; Gross and Bassell, 2014; Nygaard et al., 2014; Sontag and Sontag, 2014). (B) FMRP in APP synthesis. Aβ oligomers stimulate dendritic APP synthesis through PrPC-mGluR5 mediated protein translation dependent pathway, providing template for secretase cleavage to produce Aβ and other metabolites. A positive feedback may exist whereby production of APP results in increased substrate for amyloidogenic processing and release of Aβ, which then acitivates mGluR5 to further stimulate APP translation. In this process, FMRP competes with the other RNA binding protein hnRNP C to modulate APP translation. FMRP is a repressor of APP translation, whereas hnRNP C acts as an enhancer. The rate of APP synthesis is directly influenced by the relative association of each RNA binding protein (Lee et al., 2010). In signaling pathways, arrows indicate positive (green) or inhibitory (red) consequence on downstream components, but they do not necessarily represent direct interactions.
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Related In: Results  -  Collection

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Figure 1: Potential roles of FMRP in the pathogenesis of AD. (A) FMRP might be involved in oligomeric Aβ induced neurotoxicity. At pathological concentrations, Aβ oligomers may interact with multiple neuronal synaptic receptors such as mGluR5-PrPC, NMDARs, AMPARs, and EphB2, triggering a series of toxic synaptic events which may involve FMRP and eventually lead to synaptic dysfunction and neuronal loss. These events include: Aberrant activation of PI3K-Akt-mTORC1 and MEK-ERK signaling pathways linked to cap-dependent translation result in altered synthesis of synaptic proteins; Oligomeric Aβ exposure disrupts the balance between tau kinase (GSK3β, CaMKII, Akt, Fyn, and ERK1/2) and phosphatase (PP2A, STEP, and PTEN) activities, inducing tau hyperphosphorylation and aggregation; Stimulating EphB2-Rac1/PAK1 signaling by Aβ oligomers induces cofilin phosphorylation and actin depolymerization, leading to actin network disorganization; Binding of Aβ oligomers to PrPC-mGluR5 activates Fyn kinase which phosphorylates not only tau, but also NR2B subunit of NMDARs, enhancing NMDAR activity and causing excitotoxicity; STEP is also activated, inactivates Fyn, and dephosphorylates AMPARs and NMDARs, resulting in endocytosis of glutamate receptors, a cellular process involves Arc, PSD-95, SAPAP, and other synaptic proteins. Purple proteins are those whose mRNAs are FMRP targets (Darnell and Klann, 2013; Pasciuto and Bagni, 2014b; Santini and Klann, 2014); the blue ones are the interacting proteins of FMRP (Pasciuto and Bagni, 2014a). Proteins with red lines around them indicate those that have been successfully manipulated either pharmacologically or genetically to reverse molecular, cellular and/or behavioral phenotypes in animal models of AD (Zhang et al., 2010; Malinow, 2012; Caccamo et al., 2014; Feld et al., 2014; Hamilton et al., 2014; Llorens-Martin et al., 2014) as well as ASDs (Goebel-Goody et al., 2012; Guo et al., 2012; Won et al., 2012; Darnell and Klann, 2013; Osterweil et al., 2013; Wang and Doering, 2013; Wang, 2014). Proteins with black lines around them are the ones that have been reported to be potential targets for AD therapy (Griffin et al., 2005; Lafay-Chebassier et al., 2005; Ma et al., 2008; Cisse et al., 2011; Moriguchi, 2011; Chang et al., 2012; Gross and Bassell, 2014; Nygaard et al., 2014; Sontag and Sontag, 2014). (B) FMRP in APP synthesis. Aβ oligomers stimulate dendritic APP synthesis through PrPC-mGluR5 mediated protein translation dependent pathway, providing template for secretase cleavage to produce Aβ and other metabolites. A positive feedback may exist whereby production of APP results in increased substrate for amyloidogenic processing and release of Aβ, which then acitivates mGluR5 to further stimulate APP translation. In this process, FMRP competes with the other RNA binding protein hnRNP C to modulate APP translation. FMRP is a repressor of APP translation, whereas hnRNP C acts as an enhancer. The rate of APP synthesis is directly influenced by the relative association of each RNA binding protein (Lee et al., 2010). In signaling pathways, arrows indicate positive (green) or inhibitory (red) consequence on downstream components, but they do not necessarily represent direct interactions.
Mentions: A growing number of synaptic proteins have been proposed as potential Aβ receptors or coreceptors, which are believed to mediate Aβ induced synaptic dysfunction (Karran et al., 2011; Paula-Lima et al., 2013; Pozueta et al., 2013; Overk and Masliah, 2014). Those receptors include, but are not limited to, NMDARs, mGluR5, AMPARs, cellular prion protein (PrPC), PSD-95, and EphB2 (Lacor et al., 2004; Lauren et al., 2009; Cisse et al., 2011; Larson and Lesne, 2012; Mucke and Selkoe, 2012; Um et al., 2013; Tu et al., 2014). In fact, some of Aβ receptors (NMDARs, mGluR5, and PSD-95) and their associated scaffolding proteins and adhesion molecules such as SAPAP, Shank, Homer, and SynGAP1, are those whose mRNAs are FMRP targets (Darnell and Klann, 2013; Santini and Klann, 2014), suggesting that FMRP might be involved in initiating toxic effects of Aβ oligomers through regulating Aβ receptors (Figure 1A).

View Article: PubMed Central - PubMed

Affiliation: Faculty of Medicine, University of Toronto Toronto, ON, Canada.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Fragile X mental retardation protein (FMRP) is a RNA binding protein, the absence of which due to silencing of the FMR1 gene causes fragile X syndrome, an X-linked neurodevelopmental disorder (Bassell and Warren, ; Bhakar et al., ; Santoro et al., )... More and more potential FMRP mRNA targets and interacting proteins have been identified in the mammalian brain, supporting the critical roles of FMRP in neurodevelopment, synaptic plasticity and other neurological disorders apart from fragile X syndrome (Wang et al.,, ; Pasciuto and Bagni, ; Suhl et al., )... Fragile X syndrome, the most common monogenic cause of autism spectrum disorders (ASDs), has been leading the way for better understanding of autism and other neurodevelopmental disorders (Belmonte and Bourgeron, ; Bhakar et al., ; Banerjee et al., ; Cook et al., )... Those receptors include, but are not limited to, NMDARs, mGluR5, AMPARs, cellular prion protein (PrP), PSD-95, and EphB2 (Lacor et al., ; Lauren et al., ; Cisse et al., ; Larson and Lesne, ; Mucke and Selkoe, ; Um et al., ; Tu et al., )... In fact, some of Aβ receptors (NMDARs, mGluR5, and PSD-95) and their associated scaffolding proteins and adhesion molecules such as SAPAP, Shank, Homer, and SynGAP1, are those whose mRNAs are FMRP targets (Darnell and Klann, ; Santini and Klann, ), suggesting that FMRP might be involved in initiating toxic effects of Aβ oligomers through regulating Aβ receptors (Figure 1A)... Thus, in addition to the established role in fragile X syndrome and autism, FMRP likely contributes directly to AD pathogenesis through mGluR5 dependent APP production... As discussed above, a number of signaling pathways, including PI3K-Akt-mTORC1, MEK-ERK and PAK1 pathways, have been found to be involved in the neurodegenerative progression of AD... In addition, the FMRP targeted Aβ oligomer receptors including mGluR5 and NMDARs could be ideal therapeutic targets for AD (Figure 1A)... Particularly, pharmacological inhibition or genetic deletion of mGluR5 was recently found to rescue learning deficits, or reduce Aβ oligomers and plaques in AD mice (Um et al., ; Hamilton et al., )... The relevant kinases and phosphatases could be the FMRP targets such as GSK3β, ERK, S6K1, PP2A, PTEN, and STEP (Figure 1A)... Although the tau based treatments are encouraging, additional work are undoubtedly needed to optimize each treatment for further development of safe and effective therapies... FMRP thus, acts as a molecular link between ASDs and AD through the common signaling pathways among the diseases... Developing novel therapies directed at FMRP targets may benefit both neurodevelopmental and neurodegenerative disorders... It is now known that FMRP controls signaling pathways that could be associated with both neurodevelopmental and neurodegenerative disorders.

No MeSH data available.


Related in: MedlinePlus