The Shank3ΔC mutation impairs the molecular accumulation of and response to sleepiness, both by elevating oxidative stress responses and by blocking the age-typical upregulation of pathways that differ between juveniles and adults.
Abstract
Background Sleep problems are common in autism, emerge early in life and reduce quality of life, yet the mechanistic link between autism and poor sleep remains unclear. Human and rodent data indicate that difficulty falling asleep is a core feature of autistic insomnia, pointing to impaired responses to sleepiness as the underlying cause. We previously showed that adult mice carrying a mutation in the high-confidence autism gene Shank3 (Shank3ΔC) recapitulate this insomnia phenotype and struggle to respond to sleepiness after acute sleep deprivation. Here, we used Shank3ΔC mice to examine the molecular basis of sleepiness and how this autism-associated mutation alters it to inform understanding of sleep problems in autistic individuals. Methods This study used RNA-sequencing and bioinformatics to identify molecular targets underlying the effect of the Shank3ΔC mutation on the molecular basis of sleepiness across development in male mice. We first compared cortical genome-wide gene expression following acute sleep deprivation and recovery sleep in adult wild-type (WT) and mutant mice. We then used polysomnography and RNA-sequencing to assess the response to increased sleepiness in WT and mutant mice at postnatal days 24 and 30. Results The neurotypical response to acute sleep deprivation shifted from upregulating neuronal growth and development pathways at P24/P30 to upregulating DNA damage repair and neuronal activity-dependent transcription in adulthood. The Shank3ΔC mutation largely blocked recruitment of these pathways at P24 and in adulthood while paradoxically increasing the magnitude of the mutant response at P30. In addition, mutants consistently upregulated oxidative stress pathways linked to neurodegeneration and protein synthesis regardless of age, whereas WT animals downregulated these functions. Limitations This study examined gene expression only in male mice, used a single autism rodent model, and averaged signals across mixed cortical cell types. Future work should include females, additional autism models, and single-cell approaches in additional brain regions to further characterize the cellular effects of sleep deprivation and autism-associated mutations. Conclusions The Shank3ΔC mutation impairs the molecular accumulation of and response to sleepiness, both by elevating oxidative stress responses and by blocking the age-typical upregulation of pathways that differ between juveniles and adults.
Sleep disorders are a core feature of Angelman syndrome (AS), affecting approximately 80% of individuals. They typically manifest as insomnia and disrupted sleep-wake cycles and contribute substantially to the burden experienced by affected individuals and their families. AS is caused by loss of function of the ubiquitin protein ligase E3A (UBE3A) gene, which encodes the E3 ubiquitin ligase E6AP, a protein essential for synaptic development and function. In individuals with a maternal 15q11-q13 deletion, concomitant deletion of neighboring non-imprinted genes, including GABRB3, GABRA5, GABRG3, ATP10A, and HERC2, may also contribute to the phenotype. Evidence from animal models further indicates that UBE3A plays a key role in sleep homeostasis and circadian rhythm regulation, including through interactions with core clock genes such as BMAL1. In this narrative review, we examine the role of UBE3A in sleep regulation and outline the principal sleep disturbances observed in AS, integrating findings from both preclinical models and human studies, while also considering genotype-phenotype correlations for the main clinical manifestations. The available evidence suggests that sleep disruption may be closely linked to the core neurological and behavioral features of AS, particularly epilepsy and behavioral abnormalities, through shared pathophysiological mechanisms related to UBE3A deficiency. Early identification and management of sleep disturbances may therefore represent a potentially modifiable factor for improving behavioral outcomes, seizure control, and overall quality of life in individuals with AS. In addition, sleep measures should be considered as potentially relevant clinical endpoints in ongoing trials of emerging therapeutic strategies.
G. Terrone, M. Miano, M. Carotenuto et al.· Sleep Medicine· 0 citations
SHINE syndrome is a rare neurodevelopmental disorder caused by mutations in DLG4, which encodes the postsynaptic scaffolding protein PSD-95. Key symptoms include sleep problems, hypotonia, intellectual disability, neurological disorders, and epilepsy, hence the name 'SHINE.' Here, we developed and characterized a mouse model of SHINE syndrome carrying the patient-derived DLG4V692Wfs*12/+ variant associated with a severe form of the disorder. The mutant transcript escapes nonsense-mediated decay but results in reduced PSD-95 protein expression, faithfully reproducing the molecular phenotype observed in the patient. Behavioral analyses revealed that Dlg4V692Wfs*12/+ mice recapitulate several hallmark features of SHINE syndrome, often in a sex-specific manner. Male mutants showed deficits in learning and cognitive flexibility. Dlg4V692Wfs*12/+ mice also demonstrate trends toward altered sensory processing and socialization. Male mutants exhibited an increased proportion of short sleep bouts and compensatory longer average sleep bout length, suggesting sporadic sleep reminiscent of the patient. While spontaneous seizures were not observed, future studies will test susceptibility to provoked seizures. Together, these findings establish Dlg4V692Wfs*12/+ mice as a robust and translationally relevant model that reproduces key molecular and behavioral features of SHINE syndrome. This model provides a valuable resource for elucidating the mechanisms underlying synaptic neurodevelopmental disorders and for identifying potential therapeutic strategies.
Sharon Tamir, Jiffin Paulose, A. Nguyen et al.· Human Molecular Genetics· 0 citations
Genome-wide association studies (GWAS) have identified numerous loci for insomnia, yet functional validation of effector genes remains limited because most risk variants lie in noncoding regions, and the true causal gene is not known. Here, we use prior human cell-based variant-to-gene mapping to nominate six insomnia effector genes and test them in zebrafish, a tractable diurnal vertebrate model well-suited for sleep phenotyping. Our CRISPR-based behavioral screening identifies the MEIS1 ortholog, meis1b, as a regulator of sleep maintenance, with crispants displaying impaired nighttime-specific sleep maintenance and increased sleep latency. Comparative chromatin analyses reveal conserved regulatory architecture spanning the human insomnia-associated locus and selectively implicate meis1b, whereas the duplicated ohnolog meis1a was dispensable. Developmental profiling further shows that meis1b is expressed in cerebellar granule progenitors, paralleling human MEIS1 expression, and that its disruption impairs cerebellar development. Together, these findings establish zebrafish as an efficient vertebrate platform for functional interrogation of GWAS candidates and support an evolutionarily conserved cerebellar role for MEIS1 in sleep maintenance.
A. Zimmerman, Erika Almeraya del Valle, M. Pahl et al.· Genome Research· 0 citations
A bidirectional relationship has been proposed between sleep and Alzheimer’s disease pathology, such that disruption to sleep can lead to increases in the expression of tau or its phosphorylation. Over the long term, this can potentially lead to greater expression of neurofibrillary tangles and neurodegeneration. Neurodegenerative diseases characterized by tauopathy can often manifest with deficits in motor and spatial learning. We hypothesized that early adulthood chronic sleep disruption could accelerate tau pathology in a way that alters the trajectory of spatial and motor learning in later life. To test this hypothesis, we subjected early adulthood PS19 mice (MAPT P301S) and wildtype (WT) littermates to automated daily chronic sleep disruption (SD) vs. ad libitum sleep from 2 months to 4 months of age. A 4-day Barnes maze spatial learning task and 2-day rotarod motor learning task were conducted at 6, 8 and 10 months of age with subsequent brain neuropathological evaluation at 10–14 months prior to death. Contrary to our expectations, PS19 mice experiencing early adulthood SD displayed significantly improved spatial learning in comparison to ad libitum sleeping PS19 mice at 8 and 10 months of age, with no significant impact of early adulthood SD in WT mice. At 6 months, there was a significant impairment in offline motor change in PS19 mice compared to WT mice but without a significant effect of prior sleep condition. Early adulthood SD in PS19 mice led to increased hippocampal microglia density, without increased phagocytic microglia density, in late life compared to ad libitum sleep, suggesting sustained microglial proliferation by prior chronic SD. Similarly, TUNEL positive cells were also increased with early adulthood SD in PS19 mice, suggesting persistent DNA damage in late life. However, neither tau pathology nor histological markers for neurodegeneration were significantly different between early adulthood sleep conditions in PS19 mice tested at later life. Thus, the improvement in spatial learning in late life following early adulthood chronic SD in PS19 mice would seem disentangled from an effect on tauopathy or neurodegeneration, but whether the behavioral consequence is related to the observed changes in hippocampal microglial density remains to be mechanistically linked.
Kerly Lozano, Haris Hillery, Kenny Vetter et al.· Scientific Reports· 0 citations
Insufficient sleep disrupts cognitive and emotional functioning, yet the precise neural consequences of sleep loss and their persistence remain unclear. Here, we leverage machine learning and large neuroimaging datasets to identify a candidate neural signature that robustly distinguishes sleep-deprived from well-rested brains. We validate this signature across multiple independent datasets spanning both controlled experimental and real-world settings. The signature not only detects residual neural disturbances following a night of recovery sleep, but also demonstrates sensitivity to partial sleep deprivation. Additionally, it captures natural variations in sleep duration in the general population, independent of experimental manipulation. We further identify distributed connectivity patterns that contribute to the signature, highlighting networks vulnerable to sleep manipulations and those that are resistant or rapidly normalized after recovery sleep. The reliability and generalizability of this neural signature underscore its potential as a biomarker for understanding and monitoring the neural impacts of acute and chronic sleep loss. Researchers identified a brain connectivity pattern that reliably reflects sleep deprivation. The pattern generalized across multiple independent datasets and was associated with both experimental sleep loss and natural variation in sleep duration.
Zhenfu Wen, Edward F. Pace-Schott, P. Franzen et al.· Nature Communications· 0 citations
OBJECTIVE
This article discusses the relationship between sleep and neurodegenerative disorders.
LATEST DEVELOPMENTS
Sleep disorders disrupt neurotransmitters, facilitating the progression of neurodegenerative changes. Sleep impairment promotes amyloid-β aggregation, propagating memory impairment in neurodegenerative disorders. The use of biomarkers for early diagnosis of neurodegenerative disorders may include sleep features. Sleep apnea is associated with an increased risk of Parkinson disease.
ESSENTIAL POINTS
Sleep disorders, such as obstructive sleep apnea, are five times more likely in people with Alzheimer disease. Notably, individuals with genetic factors, including carriers of APOE4, are found to have decreased overall regulation of regions within the brain that control sleep. External factors that increase the risk of dementia include long-term use of antihistamines. The risk of mild cognitive impairment is reduced with the intake of 200 mg/d of caffeine, which aligns the circadian activity of suprachiasmatic nucleus cells. People diagnosed with idiopathic rapid eye movement (REM) sleep behavior disorders have more than a 90% risk of developing an α-synucleinopathy at 14 years follow-up.