Novel neuronal cytoplasmic inclusions in a patient carrying <scp>SCA8</scp> expansion mutation

Yokoyama, Teruo; Ishiyama, Miyako; Hasegawa, Kazuko; Uchihara, Toshiki; Yagishita, Saburo

doi:10.1111/neup.12042

Cited by 8 publications

(13 citation statements)

References 12 publications

(24 reference statements)

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“…Similar changes were found in human autopsy tissue, with evidence for demyelination and axonal degeneration in deep cerebellar white matter (Fig B). These sites of white matter pathology are positive for RAN polySer, but not for polyGln (Fig B) and are consistent with white matter abnormalities previously found by imaging and neuropathology in SCA8 patients (Kumar & Miller, ; Kim et al , ; Yokoyama et al , ). In contrast, brain regions that did not show polySer aggregates in SCA8 BAC mouse cerebellum (Fig EV3A) and human cortical white matter (Fig EV3B) did not show evidence of demyelination.…”

Section: Resultssupporting

confidence: 89%

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

et al. 2018

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Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the accumulation of CUG RNA foci, an ATG-initiated polyGln and a polyAla protein expressed by repeat-associated non-ATG (RAN) translation. Although RAN proteins have been reported in a growing number of diseases, the mechanisms and role of RAN translation in disease are poorly understood. We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity. WM regions with polySer aggregates show demyelination and axonal degeneration in SCA8 human and mouse brains. Additionally, knockdown of the eukaryotic translation initiation factor eIF3F in cells reduces steady-state levels of SCA8 polySer and other RAN proteins. Taken together, these data show polySer and WM abnormalities contribute to SCA8 and identify eIF3F as a novel modulator of RAN protein accumulation.

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Section: Resultssupporting

confidence: 89%

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

et al. 2018

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“…Neuronal loss and gliosis were found in the cranial motor nucleus with basophilic inclusions immunoreactive for TDP43, a protein causative of familial ALS. 10 These findings suggest that SCA8 occasionally affects upper and lower motor neurons, a prerequisite for a diagnosis of ALS.…”

Section: Discussionmentioning

confidence: 93%

“… 5 , 6 , 8 Several studies have suggested the involvement of upper and lower motor neurons in SCA8, but a positive association between SCA8 and ALS remains unestablished. 9 , 10 …”

mentioning

confidence: 99%

Noncoding repeat expansions for ALS in Japan are associated with the ATXN8OS gene

Hirano

Samukawa

Isono³

et al. 2018

Neurol Genet

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ObjectiveTo assess the contribution of noncoding repeat expansions in Japanese patients with amyotrophic lateral sclerosis (ALS).MethodsSporadic ALS in Western countries is frequently associated with noncoding repeat expansions in the C9ORF72 gene. Spinocerebellar ataxia type 8 (SCA8) is another noncoding repeat disease caused by expanded CTA/CTG repeats in the ATXN8OS gene. Although the involvement of upper and lower motor neurons in SCA8 has been reported, a positive association between SCA8 and ALS remains unestablished. Spinocerebellar ataxia type 36 is a recently identified disease caused by noncoding repeat expansions in the NOP56 gene and is characterized by motor neuron involvement. We collected blood samples from 102 Japanese patients with sporadic ALS and analyzed the ATXN8OS gene by the PCR–Sanger sequencing method and the C9ORF72 and NOP56 genes by repeat-primed PCR assay.ResultsThree patients with ALS (3%) had mutations in the ATXN8OS gene, whereas no patient had a mutation in the C9ORF72 or NOP56 gene. The mutation-positive patients were clinically characterized by neck weakness or bulbar-predominant symptoms. None of our patients had apparent cerebellar atrophy on MRI, but 2 had nonsymptomatic abnormalities in the white matter or putamen.ConclusionsOur finding reveals the importance of noncoding repeat expansions in Japanese patients with ALS and extends the clinical phenotype of SCA8. Three percent seems small but is still relatively large for Japan, considering that the most commonly mutated genes, including the SOD1 and SQSTM1 genes, only account for 2%–3% of sporadic patients each.

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“…The pathogenic SCA8(CUG112) transcripts formed nuclear as well as perinuclear and cytoplasmic RNA foci in the larval eye-antennal discs (Fig. 3 A), which was similar to the RNA foci formed in SCA8 diseased human brain samples(38). The toxic RNA foci were predominantly localized in the nucleus along with a few cytoplasmic RNA foci.…”

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confidence: 89%

The RNA binding KH domain of Spoonbill depletes pathogenic non-coding spinocerebellar ataxia 8 transcripts and suppresses neurodegeneration in Drosophila

Tripathi

Surabhi

Bhaskar

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Spinocerebellar ataxia 8 (SCA8) pathogenesis is a resultant of gain-of-function machinery that primarily results at the RNA level. It has been reported that expanded non-coding CTG trinucleotide repeat in the ATXN8OS transcripts leads to SCA8 coupled neurodegeneration. Targeted depletion of pathogenic SCA8 transcripts is a viable therapeutic approach. In this report we have focused on the suppression of toxic RNA gain-of-function associated with SCA8. We report suppression of SCA8 associated neurodegeneration by KH RNA binding domain of Spoonbill. KH domain suppresses pathogenic SCA8 associated phenotype in adult flies. Ectopic expression of KH domain leads to massive reduction in the number and size of SCA8 RNA foci. We show that Spoonbill interacts with toxic SCA8 transcripts via its KH domain and promotes its depletion. Till date, no attempts have been made for therapeutic intervention of SCA8 pathogenesis. Further characterization of Spoonbill KH domain may aid us in designing peptide based therapeutics for SCA8 associated neurodegeneration.

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Novel neuronal cytoplasmic inclusions in a patient carrying SCA8 expansion mutation

Cited by 8 publications

References 12 publications

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

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

Noncoding repeat expansions for ALS in Japan are associated with the ATXN8OS gene

The RNA binding KH domain of Spoonbill depletes pathogenic non-coding spinocerebellar ataxia 8 transcripts and suppresses neurodegeneration in Drosophila

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