脆弱X症候群

Local protein synthesis is a crucial process that maintains local proteostasis in neurons. A large percentage of mRNAs translated in developing neurons are associated with stalled ribosomes. FMRP, the protein lost in Fragile X syndrome, is highly enriched in RNA granules that contain stalled ribosomes. Previous examination of ribosome-protected fragments (RPFs) from stalled neuronal ribosomes identified sequences that match those found in mRNAs associated with FMRP. To investigate whether FMRP recognition of these sequences is important for determining where ribosomes stall on mRNAs, we examined RPFs isolated from P5 mice of both sexes that lack the FMRP protein. The loss of FMRP had no significant effect on the proteins associated with neuronal stalled ribosomes, on ribosome structure, or the stalling sites (locations where RPFs accumulated). There was a small, but significant decrease in the number of RPFs from mRNAs previously shown to be associated with FMRP by CLIP. Additionally, the number of neuronal RNA granules containing stalled ribosomes, as assayed by ribopuromycylation, decreased. These results suggest a role of FMRP in neuronal RNA granules that contain stalled ribosomes, though loss of FMRP does not influence where ribosomes are stalled or the formation of stalled ribosome.

Mechanisms underlying feedback learning in intellectual disability (ID) remain poorly understood. Down syndrome (DS), Fragile X syndrome (FXS), and Williams syndrome (WS) are genetic syndromes associated with ID, with distinct attention and arousal regulation profiles. Pupil dilation is a well-established index of feedback processing in typical development; little is known about these processes in non-social learning in these syndromes. Participants with DS (n = 13), FXS (n = 13), WS (n = 27), and typically developing (TD) individuals (n = 56) aged 6-60 years completed a reward contingency reversal task while eye-tracking recorded pupil dilation and gaze allocation. Data were analyzed using Bayesian mixed-effects models. All groups effectively learned from feedback, staying with rewarded options and switching after losses. WS participants performed similarly to TD participants. DS and FXS individuals showed more variable behavioral performance, indicating potential individual differences in feedback processing that warrant further investigation. Physiologically, TD individuals showed greater pupil dilation following losses than wins, whereas WS individuals showed no difference, suggesting attenuated physiological sensitivity to feedback valence. All groups tended to fixate on the previously rewarded options. This research highlights the value of combining behavioral and physiological approaches in ID research.

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.

Fragile X syndrome (FXS) is classically caused by CGG repeat expansion in the FMR1 gene leading to gene silencing. We describe two unrelated patients with clinical features consistent with FXS but harbouring distinct molecular mechanisms. The first patient had a pathogenic intronic variant in FMR1, predicted to impair protein function, and no repeat expansion. The second patient carried a complete deletion of the FMR1 gene, resulting in loss of gene expression. Both individuals presented with developmental delay, intellectual disability, and behavioural manifestations typical of FXS. These cases expand the causal heterogeneity underlying a clinically recognizable phenotype. They reinforce the concept that comprehensive molecular testing beyond repeat expansion analysis is mandatory in individuals with a strong clinical suspicion of FXS, in absence of a typical CGG triplet expansion.

LIM domain kinase 1 (LIMK1) has been identified as a promising therapeutic target for a variety of conditions, such as chronic pain, open-angle glaucoma, various cancers, schizophrenia, and Fragile X syndrome. However, identifying inhibitors that selectively inhibit LIMK1 over LIM domain kinase 2 (LIMK2) has proven to be challenging. A viable strategy to overcome this difficulty is the development of covalent inhibitors, which can offer both potency and selectivity for LIMK1 due to a reactive cysteine, C349, near the active site absent in its paralog LIMK2. Here we identify an irreversible covalent inhibitor of LIMK1 (cLIMK1i), which is highly selective for LIMK1 over both LIMK2 and a panel of over 100 kinases. A crystal structure of LIMK1 soaked with cLIMK1i reveals it is a type I inhibitor occupying the ATP-binding site with its acrylamide moiety oriented toward the P-loop where C349 resides. Computational modeling supports that the P-loop of LIMK1 can adopt a conformation compatible with covalent bond formation. Biochemical and biophysical characterization of the interaction of cLIMK1i with LIMK1 demonstrates that the covalent bond with LIMK1-C349 is essential for its potent inhibition. These results support covalent inhibition of LIMK1 as a viable strategy for selectively inhibiting LIMK1 over LIMK2 and other kinases.