Long non-coding RNA NEAT1_1 ameliorates TDP-43 toxicity in in vivo models of TDP-43 proteinopathy

Matsukawa, Koji; Kukharsky, Michail S.; Park, Sei-Kyoung; Park, Sangeun; Watanabe, Naruaki; Iwatsubo, Takeshi; Hashimoto, Tadafumi; Liebman, Susan W.; Shelkovnikova, Tatyana A.

doi:10.1080/15476286.2020.1860580

Cited by 29 publications

(25 citation statements)

References 55 publications

(85 reference statements)

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“…We generated transgenic Drosophila with silenced retinal expression of the fly hnRNPA3 ortholog, Hrb87F, and crossed this line with FUS transgenic flies. Drosophila lines with retinal overexpression of human wild-type (WT) FUS were described previously ( Matsukawa et al, 2021 ; Matsumoto et al, 2018 ); they are characterized by a marked retinal thinning (~30% reduced retinal thickness) ( Fig. 6 A, B).…”

Section: Resultsmentioning

confidence: 99%

ALS-linked cytoplasmic FUS assemblies are compositionally different from physiological stress granules and sequester hnRNPA3, a novel modifier of FUS toxicity

Litscher

Watanabe

et al. 2022

Neurobiology of Disease

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Formation of cytoplasmic RNA-protein structures called stress granules (SGs) is a highly conserved cellular response to stress. Abnormal metabolism of SGs may contribute to the pathogenesis of (neuro)degenerative diseases such as amyotrophic lateral sclerosis (ALS). Many SG proteins are affected by mutations causative of these conditions, including fused in sarcoma (FUS). Mutant FUS variants have high affinity to SGs and also spontaneously form de novo cytoplasmic RNA granules. Mutant FUS-containing assemblies (mFAs), often called “pathological SGs”, are proposed to play a role in ALS-FUS pathogenesis. However, structural differences between mFAs and physiological SGs remain largely unknown therefore it is unclear whether mFAs can functionally substitute for SGs and how they affect cellular stress responses. Here we used affinity purification to isolate mFAs and physiological SGs and compare their protein composition. We found that proteins within mFAs form significantly more physical interactions than those in SGs however mFAs fail to recruit many factors involved in signal transduction. Furthermore, we found that proteasome subunits and certain nucleocytoplasmic transport factors are depleted from mFAs, whereas translation elongation, mRNA surveillance and splicing factors as well as mitochondrial proteins are enriched in mFAs, as compared to SGs. Validation experiments for a mFA-specific protein, hnRNPA3, confirmed its RNA-dependent interaction with FUS and its sequestration into FUS inclusions in cultured cells and in a FUS transgenic mouse model. Silencing of the Drosophila hnRNPA3 ortholog was deleterious and potentiated human FUS toxicity in the retina of transgenic flies. In conclusion, we show that SG-like structures formed by mutant FUS are structurally distinct from SGs, prone to persistence, likely cannot functionally replace SGs, and affect a spectrum of cellular pathways in stressed cells. Results of our study support a pathogenic role for cytoplasmic FUS assemblies in ALS-FUS.

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Section: Resultsmentioning

confidence: 99%

ALS-linked cytoplasmic FUS assemblies are compositionally different from physiological stress granules and sequester hnRNPA3, a novel modifier of FUS toxicity

Litscher

Watanabe

et al. 2022

Neurobiology of Disease

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“…NEAT1 has a short and a long isoform, NEAT1_1 and NEAT1_2 respectively. Both transcript isoforms are elements in the structural integrity of paraspeckles, however, only NEAT1_2 is essential in the formation of the paraspeckles (Shelkovnikova et al, 2018;Matsukawa et al, 2021). NEAT1_2 consists of three domains.…”

Section: Paraspecklesmentioning

confidence: 99%

Expanding the TDP-43 Proteinopathy Pathway From Neurons to Muscle: Physiological and Pathophysiological Functions

et al. 2022

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TAR DNA-binding protein 43, mostly referred to as TDP-43 (encoded by the TARDBP gene) is strongly linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). From the identification of TDP-43 positive aggregates in the brains and spinal cords of ALS/FTD patients, to a genetic link between TARBDP mutations and the development of TDP-43 pathology in ALS, there is strong evidence indicating that TDP-43 plays a pivotal role in the process of neuronal degeneration. What this role is, however, remains to be determined with evidence ranging from gain of toxic properties through the formation of cytotoxic aggregates, to an inability to perform its normal functions due to nuclear depletion. To add to an already complex subject, recent studies highlight a role for TDP-43 in muscle physiology and disease. We here review the biophysical, biochemical, cellular and tissue-specific properties of TDP-43 in the context of neurodegeneration and have a look at the nascent stream of evidence that positions TDP-43 in a myogenic context. By integrating the neurogenic and myogenic pathological roles of TDP-43 we provide a more comprehensive and encompassing view of the role and mechanisms associated with TDP-43 across the various cell types of the motor system, all the way from brain to limbs.

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“…Recently, an increased cortical level of NEAT1_1 in mice with neuronal overexpression of TDP-43 was reported. Further overexpression studies revealed that NEAT1 can function as a suppressor of TDP-43 toxicity in Drosophila and yeast models of TDP-43 proteinopathy [ 147 ].…”

Section: Autoimmune and Neurodegenerative Disorder Pathomechanisms Ca...mentioning

confidence: 99%

Long Intergenic Noncoding RNAs Affect Biological Pathways Underlying Autoimmune and Neurodegenerative Disorders

Plewka

Raczyńska

2022

Mol Neurobiol

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Long intergenic noncoding RNAs (lincRNAs) are a class of independently transcribed molecules longer than 200 nucleotides that do not overlap known protein-coding genes. LincRNAs have diverse roles in gene expression and participate in a spectrum of biological processes. Dysregulation of lincRNA expression can abrogate cellular homeostasis, cell differentiation, and development and can also deregulate the immune and nervous systems. A growing body of literature indicates their important and multifaceted roles in the pathogenesis of several different diseases. Furthermore, certain lincRNAs can be considered potential therapeutic targets and valuable diagnostic or prognostic biomarkers capable of predicting the onset of a disease, its degree of activity, or the progression phase. In this review, we discuss possible mechanisms and molecular functions of lincRNAs in the pathogenesis of selected autoimmune and neurodegenerative disorders: multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, Huntington’s disease, Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. This summary can provide new ideas for future research, diagnosis, and treatment of these highly prevalent and devastating diseases.

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Long non-coding RNA NEAT1_1 ameliorates TDP-43 toxicity in in vivo models of TDP-43 proteinopathy

Cited by 29 publications

References 55 publications

ALS-linked cytoplasmic FUS assemblies are compositionally different from physiological stress granules and sequester hnRNPA3, a novel modifier of FUS toxicity

ALS-linked cytoplasmic FUS assemblies are compositionally different from physiological stress granules and sequester hnRNPA3, a novel modifier of FUS toxicity

Expanding the TDP-43 Proteinopathy Pathway From Neurons to Muscle: Physiological and Pathophysiological Functions

Long Intergenic Noncoding RNAs Affect Biological Pathways Underlying Autoimmune and Neurodegenerative Disorders

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