<scp>TDP</scp>‐43 accelerates deadenylation of target <scp>mRNA</scp>s by recruiting Caf1 deadenylase

Fukushima, Makoto; Hosoda, Naoe; Chifu, Kotaro; Hoshino, Shin‐ichi

doi:10.1002/1873-3468.13310

Cited by 21 publications

(15 citation statements)

References 37 publications

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“…1C), suggesting a strong preference of TDP-43 for 3′ UTR binding. This general 3′ UTR preference agrees with a previous publication (18) and has also been described for a handful of TDP-43 specific target mRNAs (19,35,36). The 3′ UTR binding also coincides with the proposed role of TDP-43 as an RNA stability and translational regulator (37,38).…”

Section: Tdp-43 Rna Targets Are Involved In Multiple Signaling Pathwasupporting

confidence: 90%

TDP-43 dysfunction restricts dendritic complexity by inhibiting CREB activation and altering gene expression

Herzog

Deshpande

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative diseases that present with similar TDP-43 pathology in patient tissue. TDP-43 is an RNA-binding protein which forms aggregates in neurons of ALS and FTD patients as well as in a subset of patients diagnosed with other neurodegenerative diseases. Despite our understanding that TDP-43 is essential for many aspects of RNA metabolism, it remains obscure how TDP-43 dysfunction contributes to neurodegeneration. Interestingly, altered neuronal dendritic morphology is a common theme among several neurological disorders and is thought to precede neurodegeneration. We previously found that both TDP-43 overexpression (OE) and knockdown (KD) result in reduced dendritic branching of cortical neurons. In this study, we used TRIBE (targets of RNA-binding proteins identified by editing) as an approach to identify signaling pathways that regulate dendritic branching downstream of TDP-43. We found that TDP-43 RNA targets are enriched for pathways that signal to the CREB transcription factor. We further found that TDP-43 dysfunction inhibits CREB activation and CREB transcriptional output, and restoring CREB signaling rescues defects in dendritic branching. Finally, we demonstrate, using RNA sequencing, that TDP-43 OE and KD cause similar changes in the abundance of specific messenger RNAs, consistent with their ability to produce similar morphological defects. Our data therefore provide a mechanism by which TDP-43 dysfunction interferes with dendritic branching, and may define pathways for therapeutic intervention in neurodegenerative diseases.

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Section: Tdp-43 Rna Targets Are Involved In Multiple Signaling Pathwasupporting

confidence: 90%

TDP-43 dysfunction restricts dendritic complexity by inhibiting CREB activation and altering gene expression

Herzog

Deshpande

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Given the high conservation between murine and human 3′UTR sequences, here we showed that TDP-43 binding to human GRN mRNA is conserved and that TDP-43 depletion upregulates GRN gene expression, suggesting that TDP-43-mediated regulation of GRN mRNA instability is also likely to be maintained in humans. Indeed, recent findings have demonstrated that TDP-43 promotes GRN mRNA instability by acting on the deadenylation process in human cell models [33]. In rodent and human models, TDP-43 is known to regulate the stability of other mRNAs, with either destabilizing ( VEGF and Tau ) [7,34] or stabilizing ( NEFL , HDAC6 and Add2 ) [35,36,37] effects.…”

Section: Discussionmentioning

confidence: 99%

Inter-Species Differences in Regulation of the Progranulin–Sortilin Axis in TDP-43 Cell Models of Neurodegeneration

Gumina

Onesto

Colombrita

et al. 2019

IJMS

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Cytoplasmic aggregates and nuclear depletion of the ubiquitous RNA-binding protein TDP-43 have been described in the autoptic brain tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD) patients and both TDP-43 loss-of-function and gain-of-function mechanisms seem to contribute to the neurodegenerative process. Among the wide array of RNA targets, TDP-43 regulates progranulin (GRN) mRNA stability and sortilin (SORT1) splicing. Progranulin is a secreted neurotrophic and neuro-immunomodulatory factor whose endocytosis and delivery to the lysosomes are regulated by the neuronal receptor sortilin. Moreover, GRN loss-of-function mutations are causative of a subset of FTLD cases showing TDP-43 pathological aggregates. Here we show that TDP-43 loss-of-function differently affects the progranulin–sortilin axis in murine and human neuronal cell models. We demonstrated that although TDP-43 binding to GRN mRNA occurs similarly in human and murine cells, upon TDP-43 depletion, a different control of sortilin splicing and protein content may determine changes in extracellular progranulin uptake that account for increased or unchanged secreted protein in murine and human cells, respectively. As targeting the progranulin–sortilin axis has been proposed as a therapeutic approach for GRN-FTLD patients, the inter-species differences in TDP-43-mediated regulation of this pathway must be considered when translating studies from animal models to patients.

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“…The relationship between TDP-43 and GRN however, is not straightforward. While studies have demonstrated that TDP-43 binds to the 3 untranslated region of GRN mRNA, promoting mRNA instability (Colombrita et al, 2012;Fukushima et al, 2019), GRN protein levels were not decreased. The observed difference in transcript and protein levels could be explained by the concurrent effect of TDP-43 on SORT1 mRNA (Gumina et al, 2019).…”

Section: Rna-binding Proteinsmentioning

confidence: 91%

Tweaking Progranulin Expression: Therapeutic Avenues and Opportunities

Terryn

Verfaillie

Damme

2021

Front. Mol. Neurosci.

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Frontotemporal dementia (FTD) is a neurodegenerative disease, leading to behavioral changes and language difficulties. Heterozygous loss-of-function mutations in progranulin (GRN) induce haploinsufficiency of the protein and are associated with up to one-third of all genetic FTD cases worldwide. While the loss of GRN is primarily associated with neurodegeneration, the biological functions of the secreted growth factor-like protein are more diverse, ranging from wound healing, inflammation, vasculogenesis, and metabolic regulation to tumor cell growth and metastasis. To date, no disease-modifying treatments exist for FTD, but different therapeutic approaches to boost GRN levels in the central nervous system are currently being developed (including AAV-mediated GRN gene delivery as well as anti-SORT1 antibody therapy). In this review, we provide an overview of the multifaceted regulation of GRN levels and the corresponding therapeutic avenues. We discuss the opportunities, advantages, and potential drawbacks of the diverse approaches. Additionally, we highlight the therapeutic potential of elevating GRN levels beyond patients with loss-of-function mutations in GRN.

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TDP‐43 accelerates deadenylation of target mRNAs by recruiting Caf1 deadenylase

Cited by 21 publications

References 37 publications

TDP-43 dysfunction restricts dendritic complexity by inhibiting CREB activation and altering gene expression

TDP-43 dysfunction restricts dendritic complexity by inhibiting CREB activation and altering gene expression

Inter-Species Differences in Regulation of the Progranulin–Sortilin Axis in TDP-43 Cell Models of Neurodegeneration

Tweaking Progranulin Expression: Therapeutic Avenues and Opportunities

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