Sleep Disorders in Hereditary Ataxias

Huebra, Lucio; Coelho, Fernando Morgadinho Santos; Filho, Flávio Moura Rezende; Barsottini, Orlando Graziani Póvoas; Pedroso, José Luiz

doi:10.1007/s11910-019-0968-1

Cited by 16 publications

(18 citation statements)

References 72 publications

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“…In terms of total duration of each state, we only observed an increase of total REM duration in Q84/Q84 mice compared with WT/WT mice (Figure 2). Importantly, we found that Q84/Q84 mice showed an increased number of bouts and shorter bout duration of REM, NREM, and WAKE compared to WT/WT mice, all p<0.05 (Figure 2), indicating increased sleep fragmentation in these mutant mice, similar to previous observations in SCA3 subjects 28, 29, 38 .…”

Section: Resultssupporting

confidence: 89%

Sleep alterations in a mouse model of Spinocerebellar ataxia type 3

Tsimpanouli

Ghimire

Barget

et al. 2022

Preprint

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BackgroundSpinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder showing progressive neuronal loss in several brain areas and a broad spectrum of motor and non-motor symptoms, including ataxia and altered sleep. While sleep disturbances are known to play pathophysiologic roles in other neurodegenerative disorders, their impact on SCA3 is unknown.ObjectivesUsing state-of-the art spectrographic measurements, we sought to quantitatively characterize sleep electroencephalography (EEG) in a SCA3 transgenic mouse model with confirmed disease phenotype.MethodsWe first measured motor phenotypes in 18–31-week-old homozygous and hemizygous SCA3 YACMJD84.2 mice and non-transgenic wild-type littermate mice during lights-on and lights-off periods. We next implanted electrodes to obtain 12-hour (zeitgeber time 0-12) EEG recordings for three consecutive days when the mice were 26–36 weeks old. We then analyzed EEG-based sleep structure data to quantify differences between homozygous, hemizygous, and wild-type mice.ResultsCompared to wild-type littermates, SCA3 homozygous mice display: i) increased duration of rapid-eye movement sleep (REM) and fragmentation in all sleep and wake states; ii) higher beta power oscillations during REM and non-REM (NREM); and iii) additional spectral power band alterations during REM and wake.ConclusionsOur data show that sleep architecture and EEG spectral power are dysregulated in homozygous SCA3 mice, indicating that common sleep-related etiologic factors may underlie mouse and human SCA3 phenotypes.

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Section: Resultssupporting

confidence: 89%

Sleep alterations in a mouse model of Spinocerebellar ataxia type 3

Tsimpanouli

Ghimire

Barget

et al. 2022

Preprint

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“…Nevertheless, it is becoming increasingly apparent that sleep disturbances are not only common among those affected by motor disorders (13,46,51,52,59,60,61,62,135,136,152), but that these disturbances are more than secondary symptoms. If we are to deeply and better understand network disorders like dystonia, we must approach future investigations into the mechanisms and potential therapies of the condition with a mindset that places the non-motor complications, such as sleep, in the same hierarchy as the visible motor complications that remain at the forefront of investigation.…”

Section: Discussionmentioning

confidence: 99%

Potential Interactions Between Cerebellar Dysfunction and Sleep Disturbances in Dystonia

Leon

Sillitoe²

2022

Dystonia

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Dystonia is the third most common movement disorder. It causes debilitating twisting postures that are accompanied by repetitive and sometimes intermittent co- or over-contractions of agonist and antagonist muscles. Historically diagnosed as a basal ganglia disorder, dystonia is increasingly considered a network disorder involving various brain regions including the cerebellum. In certain etiologies of dystonia, aberrant motor activity is generated in the cerebellum and the abnormal signals then propagate through a “dystonia circuit” that includes the thalamus, basal ganglia, and cerebral cortex. Importantly, it has been reported that non-motor defects can accompany the motor symptoms; while their severity is not always correlated, it is hypothesized that common pathways may nevertheless be disrupted. In particular, circadian dysfunction and disordered sleep are common non-motor patient complaints in dystonia. Given recent evidence suggesting that the cerebellum contains a circadian oscillator, displays sleep-stage-specific neuronal activity, and sends robust long-range projections to several subcortical regions involved in circadian rhythm regulation, disordered sleep in dystonia may result from cerebellum-mediated dysfunction of the dystonia circuit. Here, we review the evidence linking dystonia, cerebellar network dysfunction, and cerebellar involvement in sleep. Together, these ideas may form the basis for the development of improved pharmacological and surgical interventions that could take advantage of cerebellar circuitry to restore normal motor function as well as non-motor (sleep) behaviors in dystonia.

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“…These functions are dependent on the ability of ATXN2 to condense into RNA granules via its intrinsically disordered regions (IDRs). Additionally, ATXN2 has been implicated in the regulation of circadian rhythm in flies (Lim and Allada, 2013; Zhang et al, 2013) and mice (Pfeffer et al, 2017), and perturbed sleeping patterns have been observed in both SCA and ALS cases (Boentert, 2020; Huebra et al, 2019). Thus, defining the mechanisms connecting ATXN2 to condensate form and function will provide insight into this important disease gene and could suggest additional ways to safely target this function therapeutically (Auburger et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Poly(A)-binding protein is an ataxin-2 chaperone that emulsifies biomolecular condensates

Boeynaems

Dorone

Marian

et al. 2021

Preprint

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Biomolecular condensation underlies the biogenesis of an expanding array of membraneless assemblies, including stress granules (SGs) which form under a variety of cellular stresses. Advances have been made in understanding the molecular grammar that dictates the behavior of a few key scaffold proteins that make up these phases but how the partitioning of hundreds of other SG proteins is regulated remains largely unresolved. While investigating the rules that govern the condensation of ataxin-2, a SG protein implicated in neurodegenerative disease, we unexpectedly identified a short 14aa sequence that acts as an ataxin-2 condensation switch and is conserved across the eukaryote lineage. We identify poly(A)-binding proteins as unconventional RNA-dependent chaperones that control this regulatory switch. Our results uncover a hierarchy of cis and trans interactions that fine-tune ataxin-2 condensation and reveal a new molecular function for ancient poly(A)-binding proteins as emulsifiers of biomolecular condensate proteins. These findings may inspire novel approaches to therapeutically target aberrant phases in disease.

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Sleep Disorders in Hereditary Ataxias

Cited by 16 publications

References 72 publications

Sleep alterations in a mouse model of Spinocerebellar ataxia type 3

Sleep alterations in a mouse model of Spinocerebellar ataxia type 3

Potential Interactions Between Cerebellar Dysfunction and Sleep Disturbances in Dystonia

Poly(A)-binding protein is an ataxin-2 chaperone that emulsifies biomolecular condensates

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