<i>SYNE1</i> mutations cause autosomal‐recessive ataxia with retained reflexes in Brazilian patients

Gama, Maria Thereza Drumond; Houle, Gabrielle; Noreau, Anne; Dionne‐Laporte, Alexandre; Rouleau, Guy A.; Barsottini, Orlando Graziani Póvoas; Pedroso, José Luiz

doi:10.1002/mds.26810

Cited by 14 publications

(10 citation statements)

References 8 publications

(12 reference statements)

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“…The molecular function that causes central nervous system-specific defects in these ataxias is not known, although it has been shown that neurogenesis and neuronal migration are significantly impaired (Zhang et al, 2009) and that white matter and cerebellar and cortical regions of the brain are significantly disrupted in patients (Gama et al, 2018). The SYNE-1 ataxias also demonstrate extracerebellar phenotypes that are similar to neurodegenerative disease (Gama et al, 2016;Mademan et al, 2016). The most common mutations already observed to be linked with SYNE-1 ataxias cause truncations or abnormal splice junctions.…”

Section: Discussionmentioning

confidence: 99%

Syncrip/hnRNP Q is required for activity-induced Msp300/Nesprin-1 expression and new synapse formation

Titlow

Robertson

Järvelin

et al. 2020

Journal of Cell Biology

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Memory and learning involve activity-driven expression of proteins and cytoskeletal reorganization at new synapses, requiring posttranscriptional regulation of localized mRNA a long distance from corresponding nuclei. A key factor expressed early in synapse formation is Msp300/Nesprin-1, which organizes actin filaments around the new synapse. How Msp300 expression is regulated during synaptic plasticity is poorly understood. Here, we show that activity-dependent accumulation of Msp300 in the postsynaptic compartment of the Drosophila larval neuromuscular junction is regulated by the conserved RNA binding protein Syncrip/hnRNP Q. Syncrip (Syp) binds to msp300 transcripts and is essential for plasticity. Single-molecule imaging shows that msp300 is associated with Syp in vivo and forms ribosome-rich granules that contain the translation factor eIF4E. Elevated neural activity alters the dynamics of Syp and the number of msp300:Syp:eIF4E RNP granules at the synapse, suggesting that these particles facilitate translation. These results introduce Syp as an important early acting activity-dependent regulator of a plasticity gene that is strongly associated with human ataxias.

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Section: Discussionmentioning

confidence: 99%

Syncrip/hnRNP Q is required for activity-induced Msp300/Nesprin-1 expression and new synapse formation

Titlow

Robertson

Järvelin

et al. 2020

Journal of Cell Biology

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“…After reviewing the clinical phenotype of the previously published 168 SYNE1 ataxia patients, it was noted that detailed characterization of eye movements had not yet been performed, only the occurrence of gazeevoked nystagmus, slowing of saccades, broken up smooth pursuits, strabismus and square-wave jerks were reported [1][2][3][4][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study

et al. 2021

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Background SYNE1 ataxia is an autosomal recessive hereditary condition, the main characteristic features of which are gait and limb ataxia and cerebellar dysarthria. Reports have revealed that the clinical phenotype of SYNE1 ataxia is more complex than the first published cases with pure cerebellar signs indicated. The aim of this study was to characterize eye movement alterations in the first diagnosed Hungarian SYNE1 ataxia patients. Results Saccades and antisaccades were examined with an eye tracker device in 3 SYNE1 (one patient has two frameshift mutations [c.8515_8516insA, p.Met2839Asnfs*53 and c.11594_11595insG, p.Glu3866*] in a compound heterozygous state, whereas two subjects have a splicing variant [c.23146-2A > G] in a homozygous state), 6 Friedreich ataxia (FA) patients and 12 healthy controls. Besides that, detailed clinical phenotyping and comprehensive neuropsychological assessment were carried out in all patients with ataxia. In addition to the characteristic cerebellar alterations, pyramidal signs and polyneuropathy were observed at least in 2 SYNE1 ataxia patients, for which no other underlying reason was found. The eye tracking assessment revealed hypometric saccades in the longer amplitude (18.4°) saccadic paradigm in all SYNE1 patients, whereas 2 out of 3 SYNE1 subjects performed slow saccades as well. In the antisaccade task, higher incorrect ratios of antisaccades were demonstrated in SYNE1 patients compared to healthy controls, showing inverse correlation with working memory test results. The corresponding data of FA patients was dispersed over a wide range, partially overlapping with control data. Conclusions The current study draws attention to the presence of eye movement disorders in patients with SYNE1 ataxia and demonstrates that alterations in the antisaccade paradigm may be related to working memory deficits.

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“…The molecular function that causes central nervous system specific defects in these ataxias is not known, though it has been shown that neurogenesis and neuronal migration are significantly impaired (Zhang et al, 2009) and that white matter, cerebellar and cortical regions of the brain were significantly disrupted in patients (Gama et al, 2018). The SYNE-1 ataxias also demonstrate extracellebellar phenotypes that are similar to neurodegenerative disease (Gama et al, 2016;Mademan et al, 2016). The most common mutations already observed to be linked with SYNE-1 ataxias cause truncations or abnormal splice junctions.…”

Section: Discussionmentioning

confidence: 99%

Syncrip/hnRNPQ is required for activity-induced Msp300/Nesprin-1 expression and new synapse formation

Titlow

Robertson

Järvelin

et al. 2019

Preprint

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Titlow et al. find that Syncrip (hnRNPQ RNA binding protein) acts directly on msp300 to modulate activity-dependent synaptic plasticity. In vivo biophysical experiments reveal activity-dependent changes in RNP complex sizes compatible with an increase in translation at the synapse. AbstractMemory and learning involve activity-driven expression of proteins and cytoskeletal reorganisation at new synapses, often requiring post-transcriptional regulation a long distance from corresponding nuclei. A key factor expressed early in synapse formation is Msp300/Nesprin-1, which organises actin filaments around the new synapse. How Msp300 expression is regulated during synaptic plasticity is not yet known. Here, we show that the local translation of msp300 is promoted during activity-dependent plasticity by the conserved RNA binding protein Syncrip/hnRNP Q, which binds to msp300 transcripts and is essential for plasticity. Single molecule imaging shows that Syncrip is associated in vivo with msp300 mRNA in ribosome-rich particles. Elevated neural activity alters the dynamics of Syncrip RNP granules at the synapse, suggesting a change in particle composition or binding that facilitates translation. These results introduce Syncrip as an important early-acting activitydependent translational regulator of a plasticity gene that is strongly associated with human ataxias.

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SYNE1 mutations cause autosomal‐recessive ataxia with retained reflexes in Brazilian patients

Cited by 14 publications

References 8 publications

Syncrip/hnRNP Q is required for activity-induced Msp300/Nesprin-1 expression and new synapse formation

Syncrip/hnRNP Q is required for activity-induced Msp300/Nesprin-1 expression and new synapse formation

Eye-tracking-aided characterization of saccades and antisaccades in SYNE1 ataxia patients: a pilot study

Syncrip/hnRNPQ is required for activity-induced Msp300/Nesprin-1 expression and new synapse formation

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