レット症候群

Cytochrome P450 (CYP450) enzymes play critical roles in the pathophysiology of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), Rett syndrome (RTT), and attention-deficit/hyperactivity disorder (ADHD). Although traditionally associated with hepatic and intestinal xenobiotic metabolism, several CYP450 isoforms are expressed in the central nervous system, where they regulate essential pathways involving vitamin D and cholesterol-two molecules fundamental to neural development, synaptogenesis, and membrane homeostasis. The cholesterol-CYP27A1-27-hydroxycholesterol (27-OHC)-liver X receptor (LXR) axis has emerged as a critical regulator of neurodevelopment, influencing INSIG proteins, LXRs, and LDL receptors. Additionally, members of the CYP1A, CYP2B, CYP2C, and CYP3A families contribute to neuroendocrine balance and fetal brain maturation. Dysregulation of these pathways may contribute to synaptic dysfunction, neuronal hyperexcitability, and metabolic imbalance observed in NDDs. This review highlights the interplay between CYP450 enzymes, vitamin D metabolism, and cholesterol homeostasis, emphasizing their mechanistic relevance in ASD and related disorders, and discusses the therapeutic potential of targeting CYP450-mediated pathways to restore metabolic and neurodevelopmental equilibrium.

BACKGROUND: Rett syndrome (RTT), a rare neurodevelopmental disorder caused primarily by pathogenic variants in the MECP2 gene, is characterized by severe cognitive, motor, and autonomic impairments. Atypical sensory processing-including co-occurring hypo- and hyper-responsivity-is a core yet poorly understood feature. While evoked potentials (EPs) show delayed and attenuated sensory responses in RTT, the underlying mechanisms of these impairments remain unclear. Inter-trial phase coherence (ITPC), which quantifies trial-by-trial neural response consistency, offers a promising functional biomarker of variability in sensory processing. METHODS: We characterized caregiver-reported sensory responsivity in 32 individuals with RTT (all female) and 28 typically developing controls (26 female, 2 male). EPs were then recorded during passive visual and auditory stimulation and ITPC was computed to assess whether variability in the timing of neural responses could account for reduced EP amplitudes and atypical sensory responsivity. RESULTS: Hypo- and hyper-responsivity to sensory stimuli were both significantly elevated in RTT and were positively correlated, co-occurring within individuals. ITPC was significantly reduced in RTT across visual and auditory modalities and was associated with reduced EP amplitudes. Notably, reduced ITPC in visual-evoked potentials was further associated with elevated visual responsivity and greater behavioral symptom severity. CONCLUSIONS: Increased variability in neural response timing may contribute to both reduced EPs and atypical sensory responsivity in RTT, supporting ITPC as a functional biomarker. Decreased temporal precision of neural activity may explain the co-occurrence of hypo- and hyper-responsivity and provide a unifying framework for sensory dysfunction across neurodevelopmental disorders.

The ability to control the expression of human genes is a major goal in synthetic biology, enables dissection of gene function, and can be harnessed for therapeutic applications. Advances in genome editing and transcriptional engineering often result in complete gene inactivation or full transcriptional repression. However, programmable tools to dial transcription at intermediate levels remain challenging. Here, we present CRISPRtune - a synthetic fusion of MeCP2 to catalytically dead dCas9 that tunes down transcription of endogenous genes in human cells by harnessing the mild repressor activity of MeCP2. Using pooled genome-scale CRISPR screens, we tune the expression of thousands of endogenous genes and define the targeting rules of CRISPRtune in human cells. With a platform to target MeCP2 at defined genomic sites, we show the direct epigenetic changes induced by MeCP2 at gene promoters and we identify its genetic dependency partners for productive transcriptional repression. Rett syndrome-associated mutations of MeCP2 show defects for transcriptional repression due to their failure to remodel the local epigenetic landscape of target genes. Together, we present a programmable method for transcriptional tuning in mammalian cells and offer an orthogonal platform to dissect the mechanistic function of chromatin regulators in living cells.

Autism spectrum disorder (ASD) is a neurodevelopmental condition clinically defined by persistent social deficits and restricted, repetitive behavior. Several other neurodevelopmental disorders exhibit these core clinical features of ASD and are therefore classified as "syndromic ASD". Although neurons have been the primary research focus on ASD and associated syndromes, accumulating evidence highlights astrocytes as critical contributors to disease mechanisms. Astrocytes are essential for regulating synapse development, neurotransmitter balance, and neuroinflammation in the brain. In this review, we integrate evidence from studies in human tissues, patient-derived induced pluripotent stem cells and organoids, and animal models to establish a robust link between astrocytic dysfunction and ASD and associated syndromes. By systematically examining key astrocytic functions, we elucidate mechanistic pathways through which astrocytic dysregulation contributes to aberrant synaptogenesis, disrupted ion and neurotransmitter homeostasis, maladaptive neuroinflammatory signaling, and impaired metabolic coupling in ASD and associated syndromes. Finally, we discuss the potential of various astrocyte-targeted interventions, which hold promise for advancing precision medicine approaches to these devastating disorders.

Rett syndrome (RTT) is a neurodevelopmental disorder that is associated with loss-of-function mutations in the methyl CpG binding protein 2 (MECP2) gene. MECP2 regulates transcription both locally and globally, making it challenging to distinguish between genes that are pathogenic and those that constitute transcriptional noise. A rare subpopulation of patients lack MECP2 mutations despite presenting with sufficient symptoms to warrant a clinical diagnosis of RTT. These patients are classified as having atypical and MECP2 mutation-negative forms of the disorder. We hypothesized that identifying pathways with conserved disruption between typical and atypical forms of RTT would be a viable mechanism to reduce transcriptional noise and identify the genes that are most critical to their shared clinical presentation. To test this theory, we conducted differential RNA sequencing using 5 atypical RTT, 6 typical RTT (R255X), and 9 neurotypical control temporal cortex autopsy samples. Pathways associated with heat shock factor 1 (HSF1) signaling were among the most enriched in both RTT populations. Validation studies using 37 patient temporal cortex samples showed that increased HSF1 signaling was enriched in those with classically severe MECP2 mutations. To investigate whether increased HSF1 signaling is compensatory or pathogenic, we conducted in vivo hyperthermia experiments complemented by cellular stress array analyses. These experiments established that RTT model mice exhibit faster and larger induction of cellular stress-associated proteins. Pharmacological induction of HSF1 in Mecp2+/- mice was consistent with hyperthermia experiments, showing seizure-like phenotypes and lethality. Conversely, chronic inhibition of HSF1 signaling improved RTT-like phenotypes in domains of motor learning and general health. Together, these data suggest that promiscuous HSF1 signaling is likely a pathogenic amplifier of severe phenotypes and provide a rationale that inhibiting this pathology may hold therapeutic potential in RTT and related disorders. SIGNIFICANCE STATEMENT: Rett syndrome is a devastating neurodevelopmental disorder with limited therapeutic options. This manuscript identifies heat shock factor 1-signaling as a novel therapeutic target and proposes a molecular mechanism by which cellular stress responses are regulated in Rett syndrome.