Critical developmental periods of vulnerability in dystonia

Dystonia, Год журнала: 2024, Номер 3

Опубликована: Март 13, 2024

Dystonia is a heterogenous movement disorder characterised by involuntary muscle contractions, leading to abnormal postures and movements. Despite being the third most common disorder, pathophysiological mechanisms causing dystonia are incompletely understood. Isolated often caused pathogenic mutations in single genes. An emerging body of evidence suggests that at least some forms isolated have strong developmental component, with effects acting within discrete periods increased vulnerability during neurodevelopment. The extent which this feature genetically distinct dystonia, might be disrupted these periods, remains unclear. During critical development, neuronal activity instructive maturation circuits, inappropriate levels period can lead permanent defects. This review, an intentional focus on our work, outlines implicating disruptions as potential mechanism underlying inherited motor disorders general, particular.

Язык: Английский

Clinical and neurogenetic characterisation of autosomal recessive RBL2-associated progressive neurodevelopmental disorder

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 5, 2024

Abstract Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, date, clinical features have only described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects mutations detail, we identified and clinically characterized cohort 28 patients from 18 families LOF variants , including fourteen new substantially broaden molecular spectrum. The presentation affected is range neurological developmental abnormalities. Global delay intellectual disability were uniformly observed, ranging moderate profound involving lack acquisition key motor speech milestones most patients. Frequent included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements non-specific dysmorphic features. Common neuroimaging cerebral atrophy, white matter volume loss, corpus callosum hypoplasia cerebellar atrophy. In parallel, used fruit fly, Drosophila melanogaster investigate how disruption orthologueue Rbf impacts nervous system development. We found mutants recapitulate several harboring variants, alterations head brain morphology reminiscent perturbed locomotor behaviour. Surprisingly, addition its known role controlling tissue growth development, find continued expression also required fully differentiated post-mitotic neurons for normal locomotion adult-stage neuronal re-expression sufficient rescue mutant defects. Taken together, this study provides experimental basis understand genotype-phenotype correlations an -linked disorder suggests restoring through therapy approaches may ameliorate aspects patient symptoms.

Язык: Английский

Heterogeneous responses to embryonic critical period perturbations among different components of theDrosophilalarval locomotor circuit

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 16, 2024

Abstract As developing neural circuits become functional, they undergo a phase of heightened plasticity in response to intrinsic and/or extrinsic stimuli. These developmental windows are termed critical periods (CPs), because perturbations during the CP can lead lasting and significant change subsequent development, such as sub-optimal unstable networks. By contrast, same manipulations before or after does not create changes. Here, we have used Drosophila larval locomotor network study how different identified, connected elements respond perturbation, from pre-motor interneuron motoneuron, neuromuscular junction. Using heat stress an ecologically relevant stimulus, show that increasing temperature causes increased activity that, when applied CP, leads larvae crawl more slowly require longer recover electroshock-induced seizures, indicative decreased stability. Within central nervous system, find perturbation interneurons delivering synaptic drive motoneurons, which turn display reduced excitability. The peripheral junction, on other hand, maintains normal transmission, despite structural changes terminal overgrowth altered postsynaptic receptor field composition. Overall, our data demonstrate within differentially perturbation. Our results suggest underlying sequence, hierarchy, adjustment CPs, present highly tractable experimental model system with biology.

Язык: Английский