mRNA, Live and Unmasked

Akbalık, Güney; Schuman, Erin M.

doi:10.1126/science.1249623

Cited by 8 publications

(8 citation statements)

References 13 publications

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“…Perturbation of RNP granule function could induce neurotoxicity through several mechanisms. Our results strongly suggest that one, but not necessarily the only, neurotoxic effect of phase transition into irreversible higher order assemblies is to disrupt the function of cytoplasmic RNP granules, thereby reducing new protein synthesis in intracellular compartments, such as axon terminals, that are heavily dependent on local translation control by RNP granules ( Akbalik and Schuman, 2014 , Holt and Schuman, 2013 , Jung et al., 2014 ). This effect would be predicted to be most severe in dendrites and axon terminals of long projection neurons (e.g., motor neurons affected in ALS).…”

Section: Discussionmentioning

confidence: 67%

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function

Murakami

Qamar

Lin

et al. 2015

Neuron

760

872

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SummaryThe mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.

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Section: Discussionmentioning

confidence: 67%

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function

Murakami

Qamar

Lin

et al. 2015

Neuron

760

872

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“…This reduces the rate of new protein synthesis (Murakami et al, 2015). This has a systemic effect on neurons, however, the effect on axons and synapses is likely particularly detrimental, since such intracellular compartments have been shown to be heavily dependent on local translation regulation by RNP granules in mouse (Akbalik and Schuman, 2014; Holt and Schuman, 2013; Jung et al, 2014) and in C. elegans (Yan et al, 2009). Furthermore, the replacement of murine FUS with a mutated human form activates an integrated stress response and inhibit local intra-axonal protein synthesis in hippocampal neurons and sciatic nerves, resulting in synaptic dysfunction (López-Erauskin et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

An ALS-associated mutation in human FUS reduces neurotransmission fromC. elegansmotor neurons to muscles

Markert

Skoruppa

et al. 2019

Preprint

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Amytrophic lateral sclerosis (ALS) is a neurodegenerative disorder that has been associated with multiple genetic lesions, including mutations in the gene FUS (Fused in Sarcoma), an RNA/DNA-binding protein. Expression of the ALS-associated human FUS in C. elegans results in mislocalization and aggregation of FUS outside the nucleus, and leads to impaired neuromuscular behaviors. However, the mechanisms by which mutant FUS disrupts neuronal health and function remain partially understood. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. Expression of ALS-associated FUS impairs synaptic vesicle docking at neuromuscular junctions, and leads to the emergence of a population of large and electron-dense filament-filled endosomes. Electrophysiological recording of neuromuscular transmission revealed reduced transmission from motor neurons to muscles. Together, these results suggest a potential direct or indirect role of human FUS in the organization of synaptic vesicles, and reduced transmission from motor neurons to muscles. Summary statement An ALS-associated mutation in a trafficking protein disrupts the organization of the C. elegans neuromuscular junction.

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“…Within neurites, mRNAs are transported within RNP granules, which consist of mRNAs, ribosomes, translation factors and RNA binding proteins (Buffington et al, 2014;Glock et al, 2017). While mRNAs remain translationally inactive during transport within dendrites, they can be released from RNP granules in response to local activation and made available for translation at synaptic sites (reviewed in Akbalik and Schuman, 2014). Thus, RNA binding proteins play a critical role in RNP granule dynamics and, consequently, mRNA localization and translation (Kiebler and Bassell, 2006;Ayloo et al, 2017;Lim et al, 2017).…”

Section: Rnp Granule Dynamics and Transport-a Role For Tdp-43 In Mrna...mentioning

confidence: 99%

Dysregulation of Translation in TDP-43 Proteinopathies: Deficits in the RNA Supply Chain and Local Protein Production

et al. 2022

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Local control of gene expression provides critical mechanisms for regulating development, maintenance and plasticity in the nervous system. Among the strategies known to govern gene expression locally, mRNA transport and translation have emerged as essential for a neuron’s ability to navigate developmental cues, and to establish, strengthen and remove synaptic connections throughout lifespan. Substantiating the role of RNA processing in the nervous system, several RNA binding proteins have been implicated in both developmental and age dependent neurodegenerative disorders. Of these, TDP-43 is an RNA binding protein that has emerged as a common denominator in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and related disorders due to the identification of causative mutations altering its function and its accumulation in cytoplasmic aggregates observed in a significant fraction of ALS/FTD cases, regardless of etiology. TDP-43 is involved in multiple aspects of RNA processing including splicing, transport and translation. Given that one of the early events in disease pathogenesis is mislocalization from the nucleus to the cytoplasm, several studies have focused on elucidating the pathogenic role of TDP-43 in cytoplasmic translation. Here we review recent findings describing TDP-43 translational targets and potential mechanisms of translation dysregulation in TDP-43 proteinopathies across multiple experimental models including cultured cells, flies, mice and patient derived neurons.

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mRNA, Live and Unmasked

Abstract: Visualization of mRNA dynamics in live neurons reveals its release from granules at synapses during neuronal plasticity. [Also see Reports by Buxbaum et al. and Park et al. ]

Cited by 8 publications

References 13 publications

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function

An ALS-associated mutation in human FUS reduces neurotransmission fromC. elegansmotor neurons to muscles

Dysregulation of Translation in TDP-43 Proteinopathies: Deficits in the RNA Supply Chain and Local Protein Production

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