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Regulation of the Postsynaptic Compartment of Excitatory Synapses by the Actin Cytoskeleton in Health and Its Disruption in Disease.

Stefen H, Chaichim C, Power J, Fath T - Neural Plast. (2016)

Bottom Line: In this review, we are discussing key factors that regulate the structure and dynamics of the actin cytoskeleton, the major cytoskeletal building block that supports the postsynaptic compartment.Special attention is given to the complex interplay of actin-associated proteins that are found in the synaptic specialization.We then discuss our current understanding of how disruption of these cytoskeletal elements may contribute to the pathological events observed in the nervous system under disease conditions with a particular focus on Alzheimer's disease pathology.

View Article: PubMed Central - PubMed

Affiliation: Neurodegeneration and Repair Unit, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia; Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.

ABSTRACT
Disruption of synaptic function at excitatory synapses is one of the earliest pathological changes seen in wide range of neurological diseases. The proper control of the segregation of neurotransmitter receptors at these synapses is directly correlated with the intact regulation of the postsynaptic cytoskeleton. In this review, we are discussing key factors that regulate the structure and dynamics of the actin cytoskeleton, the major cytoskeletal building block that supports the postsynaptic compartment. Special attention is given to the complex interplay of actin-associated proteins that are found in the synaptic specialization. We then discuss our current understanding of how disruption of these cytoskeletal elements may contribute to the pathological events observed in the nervous system under disease conditions with a particular focus on Alzheimer's disease pathology.

No MeSH data available.


Related in: MedlinePlus

Amyloid-β disrupts the actin cytoskeleton and receptor trafficking through multiple pathways. There are many conflicting pathways through which Aβ is proposed to alter the actin cytoskeleton. These may involve both up- and downregulation of cofilin activity. Activation of RhoA by Aβ [204] antagonistically inhibits Rac1 [206], both leading to increased cofilin activity. In contrast, Aβ can cause decrease in cofilin activity via activation of Cdc42 [211]. Both active and inactive cofilin are thought to be required for the formation of cofilin rods, which lead to impairment of intracellular transport [215]. Alternatively or in addition to this, altered expression and/or processing of actin filament stabilizing proteins [217, 218] may impact the trafficking of neurotransmitter receptors.
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fig2: Amyloid-β disrupts the actin cytoskeleton and receptor trafficking through multiple pathways. There are many conflicting pathways through which Aβ is proposed to alter the actin cytoskeleton. These may involve both up- and downregulation of cofilin activity. Activation of RhoA by Aβ [204] antagonistically inhibits Rac1 [206], both leading to increased cofilin activity. In contrast, Aβ can cause decrease in cofilin activity via activation of Cdc42 [211]. Both active and inactive cofilin are thought to be required for the formation of cofilin rods, which lead to impairment of intracellular transport [215]. Alternatively or in addition to this, altered expression and/or processing of actin filament stabilizing proteins [217, 218] may impact the trafficking of neurotransmitter receptors.

Mentions: There are many conflicting pathways in which Aβ is proposed to alter actin cytoskeletal dynamics. The predominant theories involve modulation of cofilin activity. Conflicting evidence is found throughout the literature that suggests that cofilin is either activated or inhibited in response to Aβ toxicity (see Figure 2). Petratos and colleagues [204] reported an increase in active RhoA in SH-SY5Y cells treated with Aβ. RhoA activates Rho kinase II (ROCKII), which leads to the deactivation of myosin light chain kinase, dephosphorylating and thereby inhibiting the actions of LIMK [205]. Another pathway in which Aβ is proposed to increase cofilin activation is through inhibition of Rac1. RhoA activation requires deactivation of Rac1 [206]. Therefore it is suggested that Aβ induced increases of RhoA antagonistically decrease levels of Rac1. Rac1 inhibition reduces PAK1 signalling, which reduces the phosphorylation and activation of LIMK [207, 208]. This pathway is supported by findings of decreased PAK1 in the brains of AD patients [209]. Inactivation of LIMK in both pathways would result in reduced phosphorylation and as such the activation of cofilin [56]. Increased activation of cofilin may then disrupt receptor trafficking through disassembly of the actin cytoskeleton [208] and/or formation of cofilin rods [210]. Conversely, various studies suggest that Aβ ultimately inhibits cofilin activation through alternate signalling pathways. Mendoza-Naranjo and colleagues [211] found an increase in levels of GTPase Cdc42 in hippocampal neurons treated with fibrillar Aβ. Cdc42-PAK1-LIMK signalling cascades result in decreased cofilin activation [56, 212] which would have implications for actin cytoskeleton dynamics.


Regulation of the Postsynaptic Compartment of Excitatory Synapses by the Actin Cytoskeleton in Health and Its Disruption in Disease.

Stefen H, Chaichim C, Power J, Fath T - Neural Plast. (2016)

Amyloid-β disrupts the actin cytoskeleton and receptor trafficking through multiple pathways. There are many conflicting pathways through which Aβ is proposed to alter the actin cytoskeleton. These may involve both up- and downregulation of cofilin activity. Activation of RhoA by Aβ [204] antagonistically inhibits Rac1 [206], both leading to increased cofilin activity. In contrast, Aβ can cause decrease in cofilin activity via activation of Cdc42 [211]. Both active and inactive cofilin are thought to be required for the formation of cofilin rods, which lead to impairment of intracellular transport [215]. Alternatively or in addition to this, altered expression and/or processing of actin filament stabilizing proteins [217, 218] may impact the trafficking of neurotransmitter receptors.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4835652&req=5

fig2: Amyloid-β disrupts the actin cytoskeleton and receptor trafficking through multiple pathways. There are many conflicting pathways through which Aβ is proposed to alter the actin cytoskeleton. These may involve both up- and downregulation of cofilin activity. Activation of RhoA by Aβ [204] antagonistically inhibits Rac1 [206], both leading to increased cofilin activity. In contrast, Aβ can cause decrease in cofilin activity via activation of Cdc42 [211]. Both active and inactive cofilin are thought to be required for the formation of cofilin rods, which lead to impairment of intracellular transport [215]. Alternatively or in addition to this, altered expression and/or processing of actin filament stabilizing proteins [217, 218] may impact the trafficking of neurotransmitter receptors.
Mentions: There are many conflicting pathways in which Aβ is proposed to alter actin cytoskeletal dynamics. The predominant theories involve modulation of cofilin activity. Conflicting evidence is found throughout the literature that suggests that cofilin is either activated or inhibited in response to Aβ toxicity (see Figure 2). Petratos and colleagues [204] reported an increase in active RhoA in SH-SY5Y cells treated with Aβ. RhoA activates Rho kinase II (ROCKII), which leads to the deactivation of myosin light chain kinase, dephosphorylating and thereby inhibiting the actions of LIMK [205]. Another pathway in which Aβ is proposed to increase cofilin activation is through inhibition of Rac1. RhoA activation requires deactivation of Rac1 [206]. Therefore it is suggested that Aβ induced increases of RhoA antagonistically decrease levels of Rac1. Rac1 inhibition reduces PAK1 signalling, which reduces the phosphorylation and activation of LIMK [207, 208]. This pathway is supported by findings of decreased PAK1 in the brains of AD patients [209]. Inactivation of LIMK in both pathways would result in reduced phosphorylation and as such the activation of cofilin [56]. Increased activation of cofilin may then disrupt receptor trafficking through disassembly of the actin cytoskeleton [208] and/or formation of cofilin rods [210]. Conversely, various studies suggest that Aβ ultimately inhibits cofilin activation through alternate signalling pathways. Mendoza-Naranjo and colleagues [211] found an increase in levels of GTPase Cdc42 in hippocampal neurons treated with fibrillar Aβ. Cdc42-PAK1-LIMK signalling cascades result in decreased cofilin activation [56, 212] which would have implications for actin cytoskeleton dynamics.

Bottom Line: In this review, we are discussing key factors that regulate the structure and dynamics of the actin cytoskeleton, the major cytoskeletal building block that supports the postsynaptic compartment.Special attention is given to the complex interplay of actin-associated proteins that are found in the synaptic specialization.We then discuss our current understanding of how disruption of these cytoskeletal elements may contribute to the pathological events observed in the nervous system under disease conditions with a particular focus on Alzheimer's disease pathology.

View Article: PubMed Central - PubMed

Affiliation: Neurodegeneration and Repair Unit, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia; Translational Neuroscience Facility, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.

ABSTRACT
Disruption of synaptic function at excitatory synapses is one of the earliest pathological changes seen in wide range of neurological diseases. The proper control of the segregation of neurotransmitter receptors at these synapses is directly correlated with the intact regulation of the postsynaptic cytoskeleton. In this review, we are discussing key factors that regulate the structure and dynamics of the actin cytoskeleton, the major cytoskeletal building block that supports the postsynaptic compartment. Special attention is given to the complex interplay of actin-associated proteins that are found in the synaptic specialization. We then discuss our current understanding of how disruption of these cytoskeletal elements may contribute to the pathological events observed in the nervous system under disease conditions with a particular focus on Alzheimer's disease pathology.

No MeSH data available.


Related in: MedlinePlus