<scp>SCA</scp>
            8
            <scp>RAN</scp>
            polySer protein preferentially accumulates in white matter regions and is regulated by
            <scp>eIF</scp>
            3F

Ayhan, Fatma; Pérez, Bárbaro Agustín Armas; Shorrock, Hannah K.; Zu, Tao; Báñez-Coronel, Mónica; Reid, Tammy; Furuya, Hirokazu; Clark, H. Brent; Troncoso, Juan C.; Ross, Christopher A.; Subramony, S. H.; Ashizawa, Tetsuo; Wang, Eric T.; Yachnis, Anthony T.; Ranum, Laura P.W.

doi:10.15252/embj.201899023

Cited by 54 publications

(49 citation statements)

References 51 publications

(81 reference statements)

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“…When expressed on their own, polyCys and polySer exhibit little to no phenotypic consequences in C. elegans. This was surprising considering a recent study which suggested that polySer has significant toxicity in a SCA8 murine model, another CAG repeat expansion disease [50]. However, this model did not express a pure polySer protein.…”

Section: Polycys and Polyser: Weakly Toxic Ran Productsmentioning

confidence: 83%

PolyQ-independent toxicity associated with novel translational products from CAG repeat expansions

2020

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Expanded CAG nucleotide repeats are the underlying genetic cause of at least 14 incurable diseases, including Huntington's disease (HD). The toxicity associated with many CAG repeat expansions is thought to be due to the translation of the CAG repeat to create a polyQ protein, which forms toxic oligomers and aggregates. However, recent studies show that HD CAG repeats undergo a non-canonical form of translation called Repeat-associated non-AUG dependent (RAN) translation. RAN translation of the CAG sense and CUG antisense RNAs produces six distinct repeat peptides: polyalanine (polyAla, from both CAG and CUG repeats), polyserine (polySer), polyleucine (polyLeu), polycysteine (polyCys), and polyglutamine (polyGln). The toxic potential of individual CAG-derived RAN polypeptides is not well understood. We developed pure C. elegans protein models for each CAG RAN polypeptide using codon-varied expression constructs that preserve RAN protein sequence but eliminate repetitive CAG/CUG RNA. While all RAN polypeptides formed aggregates, only polyLeu was consistently toxic across multiple cell types. In GABAergic neurons, which exhibit significant neurodegeneration in HD patients, codon-varied (Leu) 38 , but not (Gln) 38 , caused substantial neurodegeneration and motility defects. Our studies provide the first in vivo evaluation of CAG-derived RAN polypeptides in a multicellular model organism and suggest that polyQ-independent mechanisms, such as RAN-translated polyLeu peptides, may have a significant pathological role in CAG repeat expansion disorders.

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Section: Polycys and Polyser: Weakly Toxic Ran Productsmentioning

confidence: 83%

PolyQ-independent toxicity associated with novel translational products from CAG repeat expansions

2020

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“…Finally, a recent study implicated eIF3 in neurodegenerative diseases marked by expansion of simple DNA repeat sequences ( Ayhan et al, 2018 ). The repeats, which are sometimes intronic, can give rise to sense and anti-sense transcripts that are translated via repeat-associated non-ATG (RAN) translation ( Zu et al, 2011 ).…”

Section: Eif3 In Diseases: Cancer and Beyondmentioning

confidence: 99%

“…A search for RAN transactivating factors that promote initiation independently of a start codon led to the demonstration that eIF3f specifically stimulates RAN translation but not ATG-dependent translation. Although the exact mechanism is still unclear, the authors proposed that eIF3f may promote RAN through an IRES-like pathway ( Ayhan et al, 2018 ). Whether this initiation function requires eIF3f within the eIF3 holo-complex is presently unknown.…”

Section: Eif3 In Diseases: Cancer and Beyondmentioning

confidence: 99%

eIF-Three to Tango: emerging functions of translation initiation factor eIF3 in protein synthesis and disease

Wolf

Lin

Duan

et al. 2020

Journal of Molecular Cell Biology

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Abstract Studies over the past three years have substantially expanded the involvements of eukaryotic initiation factor 3 (eIF3) in messenger RNA (mRNA) translation. It now appears that this multi-subunit complex is involved in every possible form of mRNA translation, controlling every step of protein synthesis from initiation to elongation, termination, and quality control in positive as well as negative fashion. Through the study of eIF3, we are beginning to appreciate protein synthesis as a highly integrated process coordinating protein production with protein folding, subcellular targeting, and degradation. At the same time, eIF3 subunits appear to have specific functions that probably vary between different tissues and individual cells. Considering the broad functions of eIF3 in protein homeostasis, it comes as little surprise that eIF3 is increasingly implicated in major human diseases and first attempts at therapeutically targeting eIF3 have been undertaken. Much remains to be learned, however, about subunit- and tissue-specific functions of eIF3 in protein synthesis and disease and their regulation by environmental conditions and post-translational modifications.

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“…Similarly, in HD, the ATG-initiated polyGln protein and four different HD RAN proteins are found in the caudate and putamen, but the HD RAN proteins show additional accumulation in the white matter bundle regions of the caudate and putamen (Bañez-Coronel et al 2015). Additionally, Ayhan et al recently described SCA8 polySer RAN protein that preferentially accumulates in cerebellar and cortical white matter regions (Ayhan et al 2018). Curiously, polySer accumulates primarily in oligodendrocyte-like cells in the white matter regions while the SCA8 polyGln and polyAla are found in Purkinje cells and other neurons.…”

Section: When and Where Ran Proteins Accumulate: Clues From The Scenementioning

confidence: 99%

Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease

Nguyen

Cleary

Ranum

2019

Annu. Rev. Neurosci.

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Microsatellite mutations involving the expansion of tri-, tetra-, penta- or hexanucleotide repeats cause more than 40 different neurological disorders. Although, traditionally, the position of the repeat within or outside of an open reading frame has been used to focus research into disease mechanisms on protein loss-of-function, protein gain-of-function or RNA gain-of- function, the discoveries of bidirectional transcription and repeat associated non-ATG (RAN) have blurred these distinctions. Here we review what is known about RAN proteins in disease, the mechanisms by which they are produced and the novel therapeutic opportunities they provide.

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SCA 8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF 3F

Cited by 54 publications

References 51 publications

PolyQ-independent toxicity associated with novel translational products from CAG repeat expansions

PolyQ-independent toxicity associated with novel translational products from CAG repeat expansions

eIF-Three to Tango: emerging functions of translation initiation factor eIF3 in protein synthesis and disease

Repeat-Associated Non-ATG Translation: Molecular Mechanisms and Contribution to Neurological Disease

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