Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response.

Animal or human models recapitulating brain ribosomopathies are incomplete, hampering development of urgently needed therapies. Here, we generated genetic mouse and human cerebral organoid models of brain ribosomopathies, caused by mutations in small nucleolar RNA (snoRNA) SNORD118. Both models exhibited protein synthesis loss, proteotoxic stress, and p53 activation and led to decreased proliferation and increased death of neural progenitor cells (NPCs), resulting in brain growth retardation, recapitulating features in human patients. Loss of SNORD118 function resulted in an aberrant upregulation of p-eIF2α, the mediator of integrated stress response (ISR). Using human iPSC cell-based screen, we identified small-molecule 2BAct, an ISR inhibitor, which potently reverses mutant NPC defects. Targeting ISR by 2BAct mitigated ribosomopathy defects in both cerebral organoid and mouse models. Thus, our SNORD118 mutant organoid and mice recapitulate human brain ribosomopathies and cross-validate maladaptive ISR as a key disease-driving mechanism, pointing to a therapeutic intervention strategy.

Ribosome biogenesis controls cranial suture MSC fate via the complement pathway in mouse and human iPSC models.

Disruption of global ribosome biogenesis selectively affects craniofacial tissues with unclear mechanisms. Craniosynostosis is a congenital craniofacial disorder characterized by premature fusion of cranial suture(s) with loss of suture mesenchymal stem cells (MSCs). Here we focused on ribosomopathy disease gene Snord118, which encodes a small nucleolar RNA (snoRNA), to genetically disturb ribosome biogenesis in suture MSCs using mouse and human induced pluripotent stem cell (iPSC) models. Snord118 depletion exhibited p53 activation, increased cell death, reduced proliferation, and premature osteogenic differentiation of MSCs, leading to suture growth and craniosynostosis defects. Mechanistically, Snord118 deficiency causes translational dysregulation of ribosomal proteins and downregulation of complement pathway genes. Further complement pathway disruption by knockout of complement C3a receptor 1 (C3ar1) exacerbated MSC and suture defects in mutant mice, whereas activating the complement pathway rescued MSC cell fate and suture growth defects. Thus, ribosome biogenesis controls MSC fate via the complement pathway to prevent craniosynostosis.

Excessive daytime sleepiness in temporomandibular disorder patients.

Objective: To investigate the relationship between excessive daytime sleepiness (EDS) and associated factors in temporomandibular disorder (TMD) patients. Methods: Medical records of 350 TMD patients were collected. The EDS status was measured by Epworth Sleepiness Scale (ESS). TMD patients were classified according to ESS scores into TMD patients with EDS (ESS ≥10) and without EDS (ESS <10). The relationship between EDS status and associated factors, such as demographic, TMD symptom severity, and psychological status was analyzed using chi-square and t-test. The level of statistical significance was set at 0.05. Results: Approximately 28.57% of TMD patients presented with EDS. These patients possessed a significantly higher level of TMD symptom severity, stress, anxiety, and depression, compared to TMD patients without EDS. Discussion: TMD patients with EDS distinctively suffer both physically and psychologically. This warrants further investigation for the causes and effects as well as underlying mechanisms of EDS in TMD.

Dental treatment as perceived etiology of temporomandibular disorders.

Objective: To characterize patients who believe their temporomandibular disorders (TMD) symptoms are caused by their prior dental treatment. Methods: A sample of 337 patients were selected and classified into dental treatment-related and non-dental treatment-related groups, according to their personal belief of their TMD etiology. The relationship between patients' perceived etiology and patient characterization was analyzed using Chi-square and t-test. Results: One-hundred and thirty-one patients perceived that the cause of their TMD was dental-related. Within this group, 27.5% of the 131 patients considered that their TMD was specifically caused by prior dental treatment. These patients possessed significantly greater disability (self-reported work disability, family interference, and higher level of depression) compared to the patients who did not believe their TMD was caused by dental treatment. Conclusion: Dentists should recognize that their dental treatments could possibly be the cause of patients' TMD symptoms, according to patients' beliefs.