Huda Yahya Zoghbi

The brain is exquisitely sensitive to methyl-CpG-binding protein 2 (MeCP2) abundance. Too little causes Rett syndrome (RTT), too much causes MECP2 duplication syndrome (MDS), and in both, severity tracks with the amount of functional MeCP2. Even modest deviations are detrimental, yet how MeCP2 abundance is controlled remains poorly understood. Using genome-wide CRISPR knockout screens, we identified hundreds of proteins regulating MeCP2, revealing a casein kinase 2 alpha 1 (CSNK2A1)-driven regulatory axis stabilizing MeCP2. We show this axis is druggable and therapeutically relevant, using a novel CSNK2A1 inhibitor in human cells and targeting Csnk2a1 in an MDS mouse model. We further connect CSNK2A1-MeCP2 regulatory disruption to Okur-Chung neurodevelopmental syndrome (OCNDS), caused by mutations in CSNK2A1 , finding ∼50% less hippocampal MeCP2 in an OCNDS mouse model. Together, these data identify a druggable regulatory axis modulating MeCP2 and implicate MeCP2 dysregulation in the molecular pathogenesis of OCNDS and potentially other neurodevelopmental disorders.

Deep brain stimulation (DBS) is associated with an increase in hippocampal neurogenesis and memory benefits, but the causal mechanism is unclear. Here, we use a mouse model of Rett syndrome, a severe learning disability syndrome caused by MECP2 loss of function, to find that DBS promotes the maturation and integration of newborn dentate granule cells (DGCs) into the neural circuit. Suppressing hippocampal neurogenesis prevented DBS from improving learning and memory. Newborn methyl-CpG-binding protein 2 (MeCP2)-deficient DGCs in Rett syndrome mice showed attenuated development and synaptic dysfunction, but DBS rescued DGC dendritic arborization, synaptogenesis, and long-term synaptic plasticity. DBS achieves this, at least in part, by increasing the protein level and shifting the phosphorylation of potassium chloride cotransporter 2, thereby restoring the conversion of GABAergic signaling from depolarization to hyperpolarization, a process that is otherwise delayed by MeCP2 deficiency. This study pinpoints one mechanism by which chronic DBS promotes neuronal maturation and enhances memory.

/SUMMARY: Many studies using mouse models of human brain disorders rely on extended recordings of brain electrical activity through electroencephalogram, or EEG. The features that researchers measure in these recordings, such as seizures and epileptiform activity, are deeply influenced by whether the animal is awake, in non-rapid eye movement (NREM) sleep, or in rapid eye movement (REM) sleep. Because total sleep duration varies naturally across animals, rigorous experimental comparisons require classifying the sleep state of every few seconds of a recording. Manual annotation is highly labor-intensive, often requiring hours per subject. While automated scoring tools accelerate this process, they are typically trained exclusively on healthy cohorts and frequently fail when applied to disease models that exhibit atypical or fragmented sleep architecture. Somnus is an open-source Python package designed to automate rodent sleep staging using EEG, muscle activity (EMG), and optional video-tracking data. It includes a robust base model trained on diverse recordings from six independent laboratories, enabling out-of-the-box classification across various equipment setups without requiring prior manual labeling. A central feature of Somnus is its capacity for rapid adaptation to pathological sleep structure. The software provides a graphical interface that directs researchers to the specific epochs where the base model is least certain. Users can manually correct these targeted epochs in a built-in viewer by comparing the model’s classification to the raw EEG signal and video, and then use their corrections to fine-tune the model. This workflow empowers researchers to generate accurate custom scorers for complex disease models or novel treatments with just a few minutes of manual correction, bypassing the need to hand-score entire experimental cohorts or develop their own models from scratch.

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) removes ~100 amino acids and accounts for approximately 10% of RTT-causing mutations. Their pathogenicity is unexpected because this C-terminal domain is dispensable in mice. Analysis of pathogenic and benign human MECP2 variants reveals that some individuals with apparently typical CTDs do not develop Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human sequence data and mouse models we show that pathogenicity results from a marked reduction in MeCP2 levels and depends on the presence of a proline proline stop motif (-PPX) generated by a shift to the +2 reading frame. CTDs that shift to the +1 frame avoid this motif and are benign. Replacing the stop codon of the PPX motif with tryptophan restores MeCP2 expression and rescues RTT-like phenotypes in a CTD mouse model. An adenine base editor efficiently introduces this substitution in cultured cells. These findings define a reliable prognostic distinction between benign and pathogenic CTDs and establish a potential editing strategy for correcting disease-causing CTD mutations.

Parkinson’s disease is characterized by dopaminergic neuron loss and accumulation of α-synuclein aggregates in the brain. G51D α-synuclein knock-in mice provide a genetically and clinically relevant model of disease, exhibiting early olfactory deficits, age-dependent motor impairment, and progressive phospho-α-synuclein accumulation. In multiple Parkinson’s disease models, striatal cholinergic and parvalbumin interneurons, as well as astrocytes, lose primary cilia and the neurotrophic signaling needed to sustain dopaminergic neurons. We show here that G51D α-synuclein mice share these phenotypes. Phospho-Ser129 α-synuclein accumulation correlates with cilia loss in cholinergic interneurons but not in spiny projection neurons that accumulate higher phospho-α-synuclein levels. In the piriform cortex, parvalbumin neurons lose primary cilia and downregulate Neurturin, potentially contributing to olfactory dysfunction. Within the peripheral olfactory epithelium, horizontal basal cells lose cilia, whereas multiciliated olfactory sensory neuron cilia remain intact. These findings reveal convergent cellular vulnerabilities across Parkinson’s disease models and highlight a pathogenic role for impaired ciliary signaling.

Many neurological diseases impact specific brain regions despite widespread expression of the disease-related protein. Spinocerebellar ataxia type 1 (SCA1) primarily affects the cerebellum, though Ataxin-1 (ATXN1) is widely expressed. We previously showed that intensified interaction between mutant ATXN1 and Capicua (CIC) drives SCA1 pathogenesis in the cerebellum, whereas ATXN1 loss augments amyloid β production in the hippocampus and cortex. CIC, however, forms a complex with ATXN1 and its paralog, Ataxin-1-like (ATXN1L), yet knockout of either yields completely different phenotypes. To determine whether this could be due to CIC having two isoforms, we generated mice bearing either the long (CIC-L) or short (CIC-S) isoform. Loss of CIC-L led to cognitive deficits, whereas loss of CIC-S caused early postnatal lethality, phenocopying ATXN1 and ATXN1L knockout mice, respectively. Furthermore, CIC-L preferentially interacts with ATXN1, and CIC-S with ATXN1L. Our data underscore the importance of isoform–paralog interplay in studying regional vulnerability in neurodegenerative diseases.

Mutations in the MECP2 gene cause the severe neurological disorder Rett syndrome. A cluster of frameshift-causing C-terminal deletions (CTDs) lead to loss of ∼100 amino acids at the C-terminus of the MeCP2 protein, and account for approximately 10% of RTT-causing mutations. The pathogenicity of C-terminal deletions (CTDs) is unexpected, as this C-terminal domain is non-essential in mice. Utilising databases of pathogenic and benign human MECP2 mutations, we find that some individuals with apparently typical CTDs do not exhibit Rett syndrome, confirming that C-terminal truncations are not intrinsically pathogenic. Using human DNA sequence data and mouse models, we demonstrate that pathogenicity results from a drastic reduction in MeCP2 levels and is determined by the presence of the short amino acid motif proline-proline-stop (-PPX) at the C-terminus, which results from a shift to the +2 reading frame. Individuals with CTDs that shift to the +1 frame avoid this motif and do not develop Rett syndrome. Mutating the stop codon of the PPX motif to tryptophan rescues MeCP2 expression and RTT-like phenotypes in a CTD mouse model. Finally, we demonstrate that an adenine base editor can efficiently introduce this tryptophan substitution in cultured cells. Overall, our findings uncover a simple and reliable prognostic distinction between benign and pathogenic CTDs and provide proof-of-concept for an editing strategy that potentially corrects all disease-causing CTD mutations.

Through cross-species genetic screens, we identified LMO7 as a regulator of tau levels in vivo . LMO7 bridges the E3 ligase CHIP and its inhibitory cochaperone BAG5, suppressing CHIP’s ligase activity and limiting tau ubiquitination and degradation. Adult LMO7 knockdown enhances CHIP activity, reduces total and phosphorylated tau, attenuates gliosis, and rescues memory deficits in tauopathy mice. Guided by AlphaFold-derived structural models and AI-based virtual screening, we developed a CHIP-derived competing peptide and identified FDA-approved drugs that disrupt the complex. Viral delivery of the peptide or oral administration of Telmisartan or MPA-2, an optimized Mycophenolic acid derivative, reduced pathogenic tau without toxicity. These findings establish CHIP–LMO7–BAG5 complex as a druggable node in tau homeostasis, with implications for tauopathies including Alzheimer’s disease, and STUB1 -associated ataxias.

Rett syndrome (RTT) is an X-linked neurological disorder caused by MECP2 mutations, creating distinct cellular environments in females (mosaic) versus males (nonmosaic). Despite female patients representing most cases, how mosaicism contributes molecularly to RTT pathogenesis, particularly in presymptomatic stages, remains poorly understood. To address this question, we profiled hippocampal transcriptomes of young female and male RTT mice using bulk and single-nucleus RNA sequencing. We identified a core disease signature of consistently dysregulated genes only in MeCP2 ⁻ cells across RTT models. Moreover, we uncovered non–cell autonomous effects exclusively in female MeCP2 ⁺ excitatory neurons, suggesting that these circuits are more vulnerable early in the mosaic RTT environment. The single-nuclei data also revealed an underappreciated MeCP2 ⁻ interneuron subtype that had the most transcriptional dysregulation in both male and female RTT hippocampi. Together, these data highlight the different effects of MeCP2 loss on excitatory and inhibitory circuits between the mosaic and nonmosaic environments in early RTT pathogenesis.

Astrocytes are key regulators of lipid metabolism, and dysregulated astrocytic lipid processing is implicated in Parkinson’s disease (PD) pathogenesis. Our prior genome-wide screens identified ACSBG1, an astrocyte-enriched acyl-CoA synthetase, as a candidate regulator of α-synuclein (α-Syn) levels. However, how ACSBG1 links lipid reprogramming to inflammatory astrocyte activation and α-Syn pathology remains unknown. We compared the transcriptomic, cytokine, and lipid secretomes of TNF-α and IL-1α stimulated primary astrocytes from wild-type (WT) and Acsbg1 knockout (KO) mice. In vivo, we crossed Acsbg1 KO mice with a Thy1-α-Syn PD model to assess behavior, neuroinflammation, synaptic integrity, and α-Syn levels. Following cytokine exposure, Acsbg1 KO astrocytes mounted an attenuated inflammatory transcriptional response, secreting significantly fewer inflammatory mediators (e.g., IL-6, RANTES, MIP-3α) and less long-chain Sphingosine 20:1 than WT astrocytes. Importantly, exogenous Sphingosine 20:1 or cytokines from WT reactive astrocytes induced neuronal α-Syn phosphorylation (pS129). In vivo, Acsbg1 deletion in Thy1-α-Syn mice reduced astrogliosis, rescued synaptic and behavioral deficits, and decreased total and pS129-α-Syn. These findings establish ACSBG1 as a key regulator of inflammatory astrocyte signaling that contributes to α-Syn phosphorylation via specific cytokine and lipid mediators, identifying ACSBG1 as a novel therapeutic target for modulating astrocyte-neuron communication in PD. Graphical