Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD

Boeynaems, Steven; Bogaert, Elke; Michiels, Emiel; Gijselinck, Ilse; Sieben, Anne; Jovicić, A; Baets, Greet De; Scheveneels, Wendy; Steyaert, Jolien; Cuijt, Ivy; Verstrepen, Kevin J.; Callaerts, Patrick; Rousseau, Frédéric; Schymkowitz, Joost; Cruts, Marc; Broeckhoven, Christine Van; Damme, Philip Van; Gitler, Aaron D.; Robberecht, Wim; Bosch, Ludo Van Den

doi:10.1038/srep20877

Cited by 257 publications

(340 citation statements)

References 29 publications

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“…Furthermore, elimination of the ATG initiation codon abolished the toxic effect of the PR construct. The finding that mostly arginine-containing DPRs display neurotoxicity in this in vivo model is in line with the findings in Drosophila [4,33] and provides evidence for a potential role of these DPRs in C9 ALS/FTD pathology. Despite the observation of GA forming abundant aggregates, it failed to induce motor axon toxicity in our model.…”

Section: Discussionsupporting

confidence: 76%

“…To this end, DPR expression constructs were designed that generate the five possible DPRs observed in C9 ALS/FTD, i.e., GA, GR, GP, PR and PA (proline-alanine), all with a length of 50 repeats. These constructs contained an ATG start codon and were codon optimized [4]. This was obtained by choosing codons so that they encode the correct amino acid, but without repeats in the RNA, thus avoiding the potential toxicity of the repeat RNA.…”

Section: Arginine-containing Ran Translation Products Induce Motor Axmentioning

confidence: 99%

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A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

et al. 2018

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The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGG GCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine-arginine and proline-arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD.

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Section: Discussionsupporting

confidence: 76%

Section: Arginine-containing Ran Translation Products Induce Motor Axmentioning

confidence: 99%

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

et al. 2018

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“…These observations suggest that the inability of the cell to tightly control these assemblies may lead to pathological aggregation. Nuclear transport is also known to deteriorate with aging [106] and is being increasingly implicated in protein aggregation diseases [69,107–112]. …”

Section: Disease Pathology and Agingmentioning

confidence: 99%

Protein Phase Separation: A New Phase in Cell Biology

Boeynaems

Alberti

Fawzi

et al. 2018

Trends in Cell Biology

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1,708

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Cellular compartments and organelles organize biological matter. Most well-known organelles are separated by a membrane boundary from their surrounding milieu. There are also many so-called membraneless organelles and recent studies suggest that these organelles, which are supramolecular assemblies of proteins and RNA molecules, form via protein phase separation. Recent discoveries have shed light on the molecular properties, formation, regulation, and function of membraneless organelles. A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.

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“…The mechanisms by which nucleocytoplasmic transport becomes disrupted range from sequestration of nuclear pore complex (NPC) molecules by toxic RNA or proteins [19, 51–56] to direct blockage of nuclear pores by toxic disease proteins [57]. Some excellent reviews on this topic have recently been published, which we recommend for detailed discussion [19, 50].…”

Section: Protein Toxicity In the Nucleusmentioning

confidence: 99%

Mechanisms of protein toxicity in neurodegenerative diseases

Chung

Lee

2018

Cell. Mol. Life Sci.

120

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Protein toxicity can be defined as all the pathological changes that ensue from accumulation, mis-localization, and/or multimerization of disease-specific proteins. Most neurodegenerative diseases manifest protein toxicity as one of their key pathogenic mechanisms, the details of which remain unclear. By systematically deconstructing the nature of toxic proteins, we aim to elucidate and illuminate some of the key mechanisms of protein toxicity from which therapeutic insights may be drawn. In this review, we focus specifically on protein toxicity from the point of view of various cellular compartments such as the nucleus and the mitochondria. We also discuss the cell-to-cell propagation of toxic disease proteins that complicates the mechanistic understanding of the disease progression as well as the spatiotemporal point at which to therapeutically intervene. Finally, we discuss selective neuronal vulnerability, which still remains largely enigmatic.

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Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD

Cited by 257 publications

References 29 publications

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

Protein Phase Separation: A New Phase in Cell Biology

Mechanisms of protein toxicity in neurodegenerative diseases

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