Protein Synthesis and Synapse Specificity in Functional Plasticity

Raghuraman, Radha; Benoy, Amrita; Sreedharan, Saji Kumar

doi:10.1093/oxfordhb/9780190686307.013.16

Cited by 4 publications

(3 citation statements)

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“…To sustain long-lasting plasticity, de novo protein synthesis is necessary [149][150][151]. Moreover, regulating PRP synthesis allows efficient utilisation of the neuron's finite resources and ensures the balance between transient and sustained plasticity.…”

Section: Epigenetics Regulates Plasticity and Taggingmentioning

confidence: 99%

Long‐term plasticity in the hippocampus: maintaining within and ‘tagging’ between synapses

2021

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Synapses between neurons are malleable biochemical structures, strengthening and diminishing over time dependent on the type of information they receive. This phenomenon known as synaptic plasticity underlies learning and memory, and its different forms, Long-Term Potentiation (LTP) and Long-Term Depression (LTD) perform varied cognitive roles in reinforcement, relearning and associating memories. Moreover, both LTP and LTD can exist in an early transient form (early-LTP/LTD) or a late persistent form (late-LTP/LTD), which are triggered by different induction protocols, and also differ in their dependence on protein synthesis and the involvement of key molecular players. Beyond homosynaptic modifications, synapses can also interact with one another. This is encapsulated in the Synaptic Tagging and Capture hypothesis (STC), where synapses expressing early-LTP/LTD present a 'tag' that can capture the protein synthesis products generated during a temporally proximal late-LTP/LTD induction. This 'tagging' phenomenon forms the framework of synaptic interactions in various conditions, and accounts for the cellular basis of the time-dependent associativity of short-lasting and long-lasting memories. All these synaptic modifications take place under controlled neuronal conditions, regulated by subcellular elements such as epigenetic regulation, proteasomal degradation and neuromodulatory signals. Here, we review current understanding of the different forms of synaptic plasticity and its regulatory mechanisms in the hippocampus, a brain region critical for memory formation. We also discuss expression of plasticity in hippocampal CA2 area, a long-overlooked narrow hippocampal subfield, and the behavioural correlate of STC. Lastly, we put forth perspectives for an integrated view of memory representation in synapses.

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Section: Epigenetics Regulates Plasticity and Taggingmentioning

confidence: 99%

Long‐term plasticity in the hippocampus: maintaining within and ‘tagging’ between synapses

2021

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“…Neuronal activity remodels the proteome of the axonal terminals (8)(9)(10). Likewise, stimulating a dendritic spine triggers unique proteome changes independently from other spines (11)(12)(13)(14). Neurons remodel local proteomes through the targeted distribution and regulation of the machinery for protein synthesis and degradation, i.e., the proteasome and autophagy system to degrade damaged and unnecessary proteins (15)(16)(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis

Alecki,

Rizwan,

et al. 2023

Preprint

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Neurons are challenged to maintain proteostasis in neuronal projections, particularly with the physiological stress at synapses to support intercellular communication underlying important functions such as memory and movement control. Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. Using high-resolution fluorescent microscopy, we discovered that neurons localize a subset of chaperone mRNAs to their dendrites, particularly more proximal regions, and increase this asymmetric localization following proteotoxic stress through microtubule-based transport from the soma. The most abundant chaperone mRNA in dendrites encodes the constitutive heat shock protein 70, HSPA8. Proteotoxic stress in cultured neurons, induced by inhibiting proteasome activity or inducing oxidative stress, enhanced transport of Hspa8 mRNAs to dendrites and the percentage of mRNAs engaged in translation on mono and polyribosomes. Knocking down the ALS-related protein Fused in Sarcoma (FUS) and a dominant mutation in the heterogenous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) impaired stress-mediated localization of Hspa8 mRNA to dendrites in cultured murine motor neurons and human iPSC-derived neurons, respectively, revealing the importance of these RNA-binding proteins in maintaining proteostasis. These results reveal the increased dendritic localization and translation of the constitutive HSP70 Hspa8 mRNA as a crucial neuronal stress response to uphold proteostasis and prevent neurodegeneration.SUMMARYLocalizing chaperones’ mRNAs in neuronal dendrites is a novel on-demand system to uphold proteostasis upon stress.

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“…Neuronal activity remodels the axonal terminal proteome [8][9][10] . Likewise, stimulating individual dendritic spines triggers unique proteome changes independently from other spines [11][12][13][14] . Neurons remodel local proteomes through the targeted distribution and regulation of the protein synthesis and degradation machinery (e.g., the proteasome and autophagy system to degrade damaged and unnecessary proteins) [15][16][17][18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis

Ugalde,

Alecki,

Rizwan

et al. 2023

Preprint

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Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discovered that neurons localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress. The most abundant dendritic chaperone mRNA encodes a constitutive heat shock protein 70 family member (HSPA8). Proteotoxic stress also enhanced HSPA8 mRNA translation efficiency in dendrites. Stress-mediated HSPA8 mRNA localization to the dendrites was impaired by depleting fused in sarcoma—an amyotrophic lateral sclerosis-related protein—in cultured mouse motor neurons and expressing a pathogenic variant of heterogenous nuclear ribonucleoprotein A2/B1 in neurons derived from human induced pluripotent stem cells. These results reveal a crucial and unexpected neuronal stress response in which RNA-binding proteins increase the dendritic localization of HSPA8 mRNA to maintain proteostasis and prevent neurodegeneration.

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Protein Synthesis and Synapse Specificity in Functional Plasticity

Cited by 4 publications

References 1 publication

Long‐term plasticity in the hippocampus: maintaining within and ‘tagging’ between synapses

Long‐term plasticity in the hippocampus: maintaining within and ‘tagging’ between synapses

Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis

Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis

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