<scp>TDP</scp>‐43 binds and transports <scp>G</scp>‐quadruplex‐containing m<scp>RNA</scp>s into neurites for local translation

Ishiguro, Akira; Kimura, Naoko; Watanabe, Yuto; Watanabe, Sumiko; Ishihama, Akira

doi:10.1111/gtc.12352

Cited by 105 publications

(136 citation statements)

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“…Loss of TDP-43 function due to nuclear clearance can lead to particular splicing signatures of disease (Polymenidou et al 2011;Xiao et al 2011;Ling et al 2015) or to defective transport of distally targeted mRNAs (Ishiguro et al 2016). Intriguingly, it has been postulated that an important function of TDP-43 is the repression of cryptic Figure 2.…”

Section: Tdp-43mentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross-disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens.

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Section: Tdp-43mentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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“…Interestingly, we could not find GR dendritic type aggregation in other parts of cortex in CNS and the majority of perinuclear aggregations of poly-GR, poly-GA and poly-GP were negative for pTDP-43 in other parts of CNS. TDP-43 is increasingly known to be involved in many neuritic functions including an essential role of mRNA transport into distal neurites [2, 17], endosomal trafficking and signaling in dendrites [46], and RNA granules in dendritic arbors [27]. Additional research will be required to find why poly-GR DPRs uniquely co-localize with pTDP-43 in dendrites.…”

Section: Discussionmentioning

confidence: 99%

Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis

et al. 2017

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Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (C9 ALS). The main hypothesized pathogenic mechanisms are C9orf72 haploinsufficiency and/or toxicity from one or more of bi-directionally transcribed repeat RNAs and their dipeptide repeat proteins (DPRs) poly-GP, poly-GA, poly-GR, poly-PR and poly-PA. Recently, nuclear import and/or export defects especially caused by arginine-containing poly-GR or poly-PR have been proposed as significant contributors to pathogenesis based on disease models. We quantitatively studied and compared DPRs, nuclear pore proteins and C9orf72 protein in clinically-related and clinically-unrelated regions of the central nervous system, and compared them to phosphorylated TDP-43 (pTDP-43), the hallmark protein of ALS. Of the five DPRs, only poly-GR was significantly abundant in clinically-related areas compared to unrelated areas (p<0.001), and formed dendritic-like aggregates in the motor cortex that co-localized with pTDP-43 (p<0.0001). While most poly-GR dendritic inclusions were pTDP-43-positive, only 4% of pTDP-43 dendritic inclusions were poly-GR-positive. Staining for arginine-containing poly-GR and poly-PR in nuclei of neurons produced signals that were not specific to C9 ALS. We could not detect significant differences of nuclear markers RanGap, Lamin B1, and Importin β1 in C9 ALS, although we observed subtle nuclear changes in ALS, both C9 and non-C9, compared to control. The C9orf72 protein itself was diffusely expressed in cytoplasm of large neurons and glia, and nearly 50% reduced, in both clinically-related frontal cortex and unrelated occipital cortex, but not in cerebellum. In summary, sense-encoded poly-GR DPR was unique, and localized to neurites and pTDP43 in motor regions of C9 ALS CNS. This is consistent with new emerging ideas about TDP-43 functions in dendrites.

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“…Notably, GGGGCC (but not CCCCGG) repeats can adopt a stable secondary structure known as a G-quadruplex, which may contribute to the persistence of this RNA species as well as its ability to reach distal neurites and associate with RNA-binding proteins in transport granules and potentially interfere with local translation 121–123 .…”

Section: The Curious Case Of C9orf72-related Als/ftdmentioning

confidence: 99%

Decoding ALS: from genes to mechanism

Taylor

Brown

Cleveland

2016

Nature

1,617

1,555

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Preface Amyotrophic lateral sclerosis (ALS) is a progressive and uniformly fatal neurodegenerative disease. A plethora of genetic factors underlying ALS have now been identified that drive motor neuron degeneration, increase susceptibility to the disease, or influence the rate of progression. Emerging themes include dysfunction in RNA metabolism and protein homeostasis, with specific defects in nucleocytoplasmic trafficking, induction of endoplasmic reticulum stress, and impaired dynamics of ribonucleoprotein bodies such as RNA granules that assemble through the process of liquid-liquid phase separation. Extraordinary recent progress in understanding the biology of ALS provides new grounds for optimism that meaningful therapies for ALS will be identified.

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TDP‐43 binds and transports G‐quadruplex‐containing mRNAs into neurites for local translation

Abstract: Growth and differentiation of the neurites depends on long-distance transport of a specific set of mRNAs to restricted area and their local translation. Here we found that a TAR DNA-binding protein of

Cited by 105 publications

References 50 publications

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis

Decoding ALS: from genes to mechanism

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