Autophagy in spinal motor neurons of conditional ADAR2-knockout mice: An implication for a role of calcium in increased autophagy flux in ALS

Sasaki, Soichi; Yamashita, Takenari; Kwak, Shin

doi:10.1016/j.neulet.2015.05.025

Cited by 13 publications

(7 citation statements)

References 20 publications

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“…On the other hand, ADAR2 expression levels were found to be down-regulated in ALS individuals, further supporting the importance of editing in proper motor neuronal functioning (Hideyama et al 2012). In addition, ADAR2 knockout mice show increased cell death rates in their motor neurons (Sasaki et al 2015), in agreement with the results observed in ALS individuals, indicating a pivotal role of A-to-I editing in proper neuronal functioning and brain development in mammals.…”

Section: Neurological Diseasessupporting

confidence: 88%

The RNA modification landscape in human disease

Jonkhout

Tran

Smith

et al. 2017

RNA

494

420

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RNA modifications have been historically considered as fine-tuning chemo-structural features of infrastructural RNAs, such as rRNAs, tRNAs, and snoRNAs. This view has changed dramatically in recent years, to a large extent as a result of systematic efforts to map and quantify various RNA modifications in a transcriptome-wide manner, revealing that RNA modifications are reversible, dynamically regulated, far more widespread than originally thought, and involved in major biological processes, including cell differentiation, sex determination, and stress responses. Here we summarize the state of knowledge and provide a catalog of RNA modifications and their links to neurological disorders, cancers, and other diseases. With the advent of direct RNA-sequencing technologies, we expect that this catalog will help prioritize those RNA modifications for transcriptome-wide maps.

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Section: Neurological Diseasessupporting

confidence: 88%

The RNA modification landscape in human disease

Jonkhout

Tran

Smith

et al. 2017

RNA

494

420

View full text Add to dashboard Cite

show abstract

“…Of these, GluA2 is responsible for Ca 2+ permeability by two mechanisms: its presence within the AMPA receptor and also by the process of RNA editing at the Q/R site by the enzyme adenosine deaminase acting on RNA 2 (ADAR2; Gallo et al, 2017; Wright & Vissel, 2012). Indeed, a growing body of evidence indicates a deficiency in RNA editing at the GluA2 Q/R site may lead to motor neuron vulnerability in ALS (Moore et al, 2019; Sasaki et al, 2015; Yamashita & Kwak, 2019). Recent findings have also shown up‐regulation of GluA1 but decreased levels of GluA2 and GluA3 within the prefrontal cortex of sporadic ALS patients (Gregory et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Riluzole does not ameliorate disease caused by cytoplasmic TDP‐43 in a mouse model of amyotrophic lateral sclerosis

Wright

Gatta

Shen

et al. 2021

Eur J of Neuroscience

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS, and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP‐43), and understanding the effects of riluzole in models that closely recapitulate TDP‐43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in female transgenic mice that inducibly express nuclear localisation sequence (NLS)‐deficient human TDP‐43 in neurons (NEFH‐tTA/tetO‐hTDP‐43ΔNLS, ‘rNLS8’, mice). Riluzole treatment from the first day of hTDP‐43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP‐43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8 mice, riluzole did not ameliorate this disease‐associated molecular phenotype. Likewise, riluzole did not alter the disease‐associated atrophy of hindlimb muscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late‐stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre‐type changes reminiscent of ALS in female rNLS8 mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways related to accumulation of TDP‐43 pathology may be needed to develop better treatments for ALS.

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“…In fact, accumulation of large defective mitochondria has been associated with cell senescence/ageing and with PD, in fact brain belonging to PD patients present reduced expression of autophagy protein6162. Some forms of MN disorders are characterized by autophagy impairment, which reduces their capacity to maintain protein homeostasis, and results in eventual neuronal cell loss6364, although a causal relationship between autophagic dysfunction and disease has not been fully established. As showed in other MN disease, our data indicated that one possible pathogenetic mechanism in BVVL-MN degeneration is their incapacity to effectively cope with increased damage to the mitochondria, leading to cell apoptosis/necrosis.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide RNA-seq of iPSC-derived motor neurons indicates selective cytoskeletal perturbation in Brown–Vialetto disease that is partially rescued by riboflavin

Rizzo

Ramirez

Compagnucci

et al. 2017

Sci Rep

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Riboflavin is essential in numerous cellular oxidation/reduction reactions but is not synthesized by mammalian cells. Riboflavin absorption occurs through the human riboflavin transporters RFVT1 and RFVT3 in the intestine and RFVT2 in the brain. Mutations in these genes are causative for the Brown–Vialetto–Van Laere (BVVL), childhood-onset syndrome characterized by a variety of cranial nerve palsies as well as by spinal cord motor neuron (MN) degeneration. Why mutations in RFVTs result in a neural cell–selective disorder is unclear. As a novel tool to gain insights into the pathomechanisms underlying the disease, we generated MNs from induced pluripotent stem cells (iPSCs) derived from BVVL patients as an in vitro disease model. BVVL-MNs explained a reduction in axon elongation, partially improved by riboflavin supplementation. RNA sequencing profiles and protein studies of the cytoskeletal structures showed a perturbation in the neurofilament composition in BVVL-MNs. Furthermore, exploring the autophagy–lysosome pathway, we observed a reduced autophagic/mitophagic flux in patient MNs. These features represent emerging pathogenetic mechanisms in BVVL-associated neurodegeneration, partially rescued by riboflavin supplementation. Our data showed that this therapeutic strategy could have some limits in rescuing all of the disease features, suggesting the need to develop complementary novel therapeutic strategies.

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Autophagy in spinal motor neurons of conditional ADAR2-knockout mice: An implication for a role of calcium in increased autophagy flux in ALS

Cited by 13 publications

References 20 publications

The RNA modification landscape in human disease

The RNA modification landscape in human disease

Riluzole does not ameliorate disease caused by cytoplasmic TDP‐43 in a mouse model of amyotrophic lateral sclerosis

Genome-wide RNA-seq of iPSC-derived motor neurons indicates selective cytoskeletal perturbation in Brown–Vialetto disease that is partially rescued by riboflavin

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