RAN Translation of the Expanded CAG Repeats in the SCA3 Disease Context

Jazurek-Ciesiolka, Magdalena; Ciesiolka, Adam; Komur, Alicja A.; Urbanek-Trzeciak, Martyna Olga; Krzyżosiak, Włodzimierz J.; Fiszer, Agnieszka

doi:10.1016/j.jmb.2020.10.033

Cited by 20 publications

(13 citation statements)

References 100 publications

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“…The existence of RAN proteins from the genes for polyQ diseases has been proven using cell models 18 , animal models and human tissues. Animal studies have included SCA8 and myotonic dystrophy type 1 (DM1) 29 .…”

Section: Discussionmentioning

confidence: 99%

“…Accumulation of SCA8 polyA and DM1 polyQ have been observed in previously established mouse models 29 . Endogenous RAN proteins have been reported to exert toxicity in various models 17 , 18 . In contrast, we explored the potential toxicity of exogenous RAN proteins in recipient cells.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, neuronal loss, apoptosis and microglial activation were observed in these brain regions, and the individual RAN protein with a C-terminal region was found to be toxic to neurons 17 . Likewise, RAN proteins with polyQ and polyA were reported to be generated from the ataxin 3 gene, a gene responsible for spinocerebellar ataxia (SCA) type 3, and the RAN proteins induced apoptosis 18 . These observations indicate that endogenous RAN proteins are toxic.…”

Section: Introductionmentioning

confidence: 99%

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Exogenous polyserine and polyleucine are toxic to recipient cells

Owada

Mitsui

Nakamura

2022

Sci Rep

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Repeat-associated non-AUG (RAN) translation of mRNAs/transcripts responsible for polyglutamine (polyQ) diseases may generate peptides containing different mono amino acid tracts such as polyserine (polyS) and polyleucine (polyL). The propagation of aggregated polyQ from one cell to another is also an intriguing feature of polyQ proteins. However, whether the RAN translation-related polyS and polyL have the ability to propagate remains unclear, and if they do, whether the exogenous polyS and polyL exert toxicity on the recipient cells is also not known yet. In the present study, we found that aggregated polyS and polyL peptides spontaneously enter neuron-like cells and astrocytes in vitro. Aggregated polyS led to the degeneration of the differentiated neuron-like cultured cells. Likewise, the two types of aggregates taken up by astrocytes induced aberrant differentiation and cell death in vitro. Furthermore, injection of each of the two types of aggregates into the ventricles of adult mice resulted in their behavioral changes. The polyS-injected mice showed extensive vacuolar degeneration in the brain. Thus, the RAN translation-related proteins containing polyS and polyL have the potential to propagate and the proteins generated by all polyQ diseases might exert universal toxicity in the recipient cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exogenous polyserine and polyleucine are toxic to recipient cells

Owada

Mitsui

Nakamura

2022

Sci Rep

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“…This bears the advantage to increase the stability of the resulting polyQ tract [ 53 ], which has not changed in our model since the first measurements of the fragment length in 2015. A disadvantage of the interrupted repeat, however, is that our mice could miss the feature of potential RNA toxicity, that is less prominent in interrupted repeats and can also contribute to disease progression [ 54 , 55 ]. Further, it is not possible to assess the impact of repeat associated non-ATG (RAN) translation, which might also play a role in SCA3, but could be extenuated in our 304Q KI mice.…”

Section: Discussionmentioning

confidence: 99%

A Novel SCA3 Knock-in Mouse Model Mimics the Human SCA3 Disease Phenotype Including Neuropathological, Behavioral, and Transcriptional Abnormalities Especially in Oligodendrocytes

et al. 2021

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Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide, caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyglutamine (polyQ)-expansion in the corresponding protein. The disease is characterized by neuropathological, phenotypical, and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed for a better understanding of the disease pathomechanisms. Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing a heterozygous or homozygous expansion of 304 CAACAGs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. We compared neuropathological, and behavioral features of the new knock-in model with the in SCA3 research mostly used YAC84Q mouse model. Further, we compared transcriptional changes found in cerebellar samples of the SCA3 knock-in mice and post-mortem human SCA3 patients. The novel knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, the mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.

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“…FXTAS CGG-repeats within the 5′-UTR of FMR1 initiate RAN translation of FMRpolyG at a near-cognate ACG codon embedded in a putative Kozak element 32 nucleotides upstream of the repeats in the +1 reading frame, while FMRpolyA initiates at a non-cognate GCG codon within the repeats in a +2 reading frame [ 47 , 48 ]. Mass spectrometry analysis also indicated that polyA RAN-translated proteins from the SCA8 CAG repeats are initiated at non-cognate GCA codons throughout the repeat tract [ 45 ] while non-cognate CUU and ACU codons are used to initiate RAN translation of polyQ upstream of the SCA3 CAG repeats and polyA proteins likely within the repeats [ 108 ] in transfected cell models. Sense C9ORF72 -repeat transcripts initiate RAN translation with a Met-tRNAi Met through eIF2A at a Kozak-embedded CUG codon located 24 nucleotides upstream of the repeat sequence in the +1 reading frame of transfected reporter constructs [ 91 , 92 , 109 ].…”

Section: Mechanisms Of Ran Translationmentioning

confidence: 99%

Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders

Castelli

Huang

Lin

et al. 2021

Biochemical Society Transactions

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Repeat-associated non-AUG (RAN) translation was discovered in 2011 in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1). This non-canonical form of translation occurs in all reading frames from both coding and non-coding regions of sense and antisense transcripts carrying expansions of trinucleotide to hexanucleotide repeat sequences. RAN translation has since been reported in 7 of the 53 known microsatellite expansion disorders which mainly present with neurodegenerative features. RAN translation leads to the biosynthesis of low-complexity polymeric repeat proteins with aggregating and cytotoxic properties. However, the molecular mechanisms and protein factors involved in assembling functional ribosomes in absence of canonical AUG start codons remain poorly characterised while secondary repeat RNA structures play key roles in initiating RAN translation. Here, we briefly review the repeat expansion disorders, their complex pathogenesis and the mechanisms of physiological translation initiation together with the known factors involved in RAN translation. Finally, we discuss research challenges surrounding the understanding of pathogenesis and future directions that may provide opportunities for the development of novel therapeutic approaches for this group of incurable neurodegenerative diseases.

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RAN Translation of the Expanded CAG Repeats in the SCA3 Disease Context

Cited by 20 publications

References 100 publications

Exogenous polyserine and polyleucine are toxic to recipient cells

Exogenous polyserine and polyleucine are toxic to recipient cells

A Novel SCA3 Knock-in Mouse Model Mimics the Human SCA3 Disease Phenotype Including Neuropathological, Behavioral, and Transcriptional Abnormalities Especially in Oligodendrocytes

Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders

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