RESUMEN
Neurons rely on mitochondrial energy metabolism for essential functions like neurogenesis, neurotransmission, and synaptic plasticity. Mitochondrial dysfunctions are associated with neurodevelopmental disorders including Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, which also presents with motor skill deficits. However, the precise role of mitochondria in the pathophysiology of FXS remains largely unknown. Notably, previous studies have linked the serotonergic system and mitochondrial activity to FXS. Our study investigates the potential therapeutic role of serotonin receptor 1A (5-HT1A) in FXS. Using the Drosophila model of FXS, we demonstrated that treatment with eltoprazine, a 5-HT1A agonist, can ameliorate synaptic transmission, correct mitochondrial deficits, and ultimately improve motor behavior. While these findings suggest that the 5-HT1A-mitochondrial axis may be a promising therapeutic target, further investigation is needed in the context of FXS.
Asunto(s)
Modelos Animales de Enfermedad , Síndrome del Cromosoma X Frágil , Mitocondrias , Receptor de Serotonina 5-HT1A , Animales , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Drosophila , Piperazinas/farmacología , Transmisión Sináptica/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico , Drosophila melanogaster/efectos de los fármacos , Actividad Motora/efectos de los fármacosRESUMEN
BACKGROUND: 15q11.2 deletions and duplications have been linked to autism spectrum disorder, schizophrenia, and intellectual disability. Recent evidence suggests that dysfunctional CYFIP1 (cytoplasmic FMR1 interacting protein 1) contributes to the clinical phenotypes observed in individuals with 15q11.2 deletion/duplication syndrome. CYFIP1 plays crucial roles in neuronal development and brain connectivity, promoting actin polymerization and regulating local protein synthesis. However, information about the impact of single nucleotide variants in CYFIP1 on neurodevelopmental disorders is limited. METHODS: Here, we report a family with 2 probands exhibiting intellectual disability, autism spectrum disorder, spastic tetraparesis, and brain morphology defects and who carry biallelic missense point mutations in the CYFIP1 gene. We used skin fibroblasts from one of the probands, the parents, and typically developing individuals to investigate the effect of the variants on the functionality of CYFIP1. In addition, we generated Drosophila knockin mutants to address the effect of the variants in vivo and gain insight into the molecular mechanism that underlies the clinical phenotype. RESULTS: Our study revealed that the 2 missense variants are in protein domains responsible for maintaining the interaction within the wave regulatory complex. Molecular and cellular analyses in skin fibroblasts from one proband showed deficits in actin polymerization. The fly model for these mutations exhibited abnormal brain morphology and F-actin loss and recapitulated the core behavioral symptoms, such as deficits in social interaction and motor coordination. CONCLUSIONS: Our findings suggest that the 2 CYFIP1 variants contribute to the clinical phenotype in the probands that reflects deficits in actin-mediated brain development processes.
Asunto(s)
Trastorno del Espectro Autista , Discapacidad Intelectual , Humanos , Discapacidad Intelectual/genética , Actinas/genética , Actinas/metabolismo , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Polimerizacion , Proteínas Adaptadoras Transductoras de Señales/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismoRESUMEN
Sleep behavior is conserved throughout evolution, and sleep disturbances are a frequent comorbidity of neuropsychiatric disorders. However, the molecular basis underlying sleep dysfunctions in neurological diseases remains elusive. Using a model for neurodevelopmental disorders (NDDs), the Drosophila Cytoplasmic FMR1 interacting protein haploinsufficiency (Cyfip85.1/+), we identify a mechanism modulating sleep homeostasis. We show that increased activity of the sterol regulatory element-binding protein (SREBP) in Cyfip85.1/+ flies induces an increase in the transcription of wakefulness-associated genes, such as the malic enzyme (Men), causing a disturbance in the daily NADP+/NADPH ratio oscillations and reducing sleep pressure at the night-time onset. Reduction in SREBP or Men activity in Cyfip85.1/+ flies enhances the NADP+/NADPH ratio and rescues the sleep deficits, indicating that SREBP and Men are causative for the sleep deficits in Cyfip heterozygous flies. This work suggests modulation of the SREBP metabolic axis as a new avenue worth exploring for its therapeutic potential in sleep disorders.
Asunto(s)
Proteínas de Drosophila , Proteínas de Unión a los Elementos Reguladores de Esteroles , Animales , Proteínas de Unión a los Elementos Reguladores de Esteroles/metabolismo , NADP/metabolismo , Drosophila/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Sueño , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Proteínas de Drosophila/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X FrágilRESUMEN
Neurodevelopmental disorders (NDDs) include a large number of conditions such as Fragile â¯X â¯syndrome, autism spectrum disorders and Down syndrome, among others. They are characterized by limitations in adaptive and social behaviors, as well as intellectual disability (ID). Whole-exome and whole-genome sequencing studies have highlighted a large number of NDD/ID risk genes. To dissect the genetic causes and underlying biological pathways, in vivo experimental validation of the effects of these mutations is needed. The fruit fly, Drosophila melanogaster, is an ideal model to study NDDs, with highly tractable genetics, combined with simple behavioral and circuit assays, permitting rapid medium-throughput screening of NDD/ID risk genes. Here, we review studies where the use of well-established assays to study mechanisms of learning and memory in Drosophila has permitted insights into molecular mechanisms underlying IDs. We discuss how technologies in the fly model, combined with a high degree of molecular and physiological conservation between flies and mammals, highlight the Drosophila system as an ideal model to study neurodevelopmental disorders, from genetics to behavior.
Asunto(s)
Discapacidad Intelectual , Trastornos del Neurodesarrollo , Animales , Drosophila , Drosophila melanogaster , Discapacidad Intelectual/genética , MemoriaRESUMEN
Social impairment is frequently associated with mitochondrial dysfunction and altered neurotransmission. Although mitochondrial function is crucial for brain homeostasis, it remains unknown whether mitochondrial disruption contributes to social behavioral deficits. Here, we show that Drosophila mutants in the homolog of the human CYFIP1, a gene linked to autism and schizophrenia, exhibit mitochondrial hyperactivity and altered group behavior. We identify the regulation of GABA availability by mitochondrial activity as a biologically relevant mechanism and demonstrate its contribution to social behavior. Specifically, increased mitochondrial activity causes gamma aminobutyric acid (GABA) sequestration in the mitochondria, reducing GABAergic signaling and resulting in social deficits. Pharmacological and genetic manipulation of mitochondrial activity or GABA signaling corrects the observed abnormalities. We identify Aralar as the mitochondrial transporter that sequesters GABA upon increased mitochondrial activity. This study increases our understanding of how mitochondria modulate neuronal homeostasis and social behavior under physiopathological conditions.
Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Proteínas de Drosophila/metabolismo , Mitocondrias/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Animales Modificados Genéticamente , Ácido Aspártico/metabolismo , Calcio/metabolismo , Proteínas de Unión al Calcio/fisiología , Proteínas de Drosophila/fisiología , Drosophila melanogaster/metabolismo , Glucosa/metabolismo , Homeostasis , Humanos , Masculino , Mitocondrias/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas Mitocondriales/metabolismo , Neuronas/metabolismo , Conducta Social , Transmisión Sináptica , Ácido gamma-Aminobutírico/genéticaRESUMEN
Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders ("synaptopathies"). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data (https://syngoportal.org and http://geneontology.org).
Asunto(s)
Encéfalo/citología , Ontología de Genes , Proteómica , Programas Informáticos , Sinapsis/fisiología , Animales , Encéfalo/fisiología , Bases de Datos Genéticas , Humanos , Bases del Conocimiento , Potenciales Sinápticos/fisiología , SinaptosomasRESUMEN
Adult, circuit-integrated neurons must be maintained and supported for the life span of their host. The attenuation of either maintenance or plasticity leads to impaired circuit function and ultimately to neurodegenerative disorders. Over the last few years, significant discoveries of molecular mechanisms were made that mediate the formation and maintenance of axons. Here, we highlight intrinsic and extrinsic mechanisms that ensure the health and survival of axons. We also briefly discuss examples of mutations associated with impaired axonal maintenance identified in specific neurological conditions. A better understanding of these mechanisms will therefore help to define targets for therapeutic interventions.
Asunto(s)
Axones/metabolismo , Transporte Biológico/fisiología , Mitocondrias/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Trastornos del Neurodesarrollo/metabolismo , Neuroglía/metabolismo , Animales , HumanosRESUMEN
The review is an overview of the current knowledge of neuronal regeneration properties in mammals and fish. The ability to regenerate the damaged parts of the nervous tissue has been demonstrated in all vertebrates. Notably, fish and amphibians have the highest capacity for neurogenesis, whereas reptiles and birds are able to only regenerate specific regions of the brain, while mammals have reduced capacity for neurogenesis. Zebrafish (Danio rerio) is a promising model of study because lesions in the brain or complete cross-section of the spinal cord are followed by an effective neuro-regeneration that successfully restores the motor function. In the brain and the spinal cord of zebrafish, stem cell activity is always able to re-activate the molecular programs required for central nervous system regeneration. In mammals, traumatic brain injuries are followed by reduced neurogenesis and poor axonal regeneration, often insufficient to functionally restore the nervous tissue, while spinal injuries are not repaired at all. The environment that surrounds the stem cell niche constituted by connective tissue and stimulating factors, including pro-inflammation molecules, seems to be a determinant in triggering stem cell proliferation and/or the trans-differentiation of connective elements (mainly fibroblasts). Investigating and comparing the neuronal regeneration in zebrafish and mammals may lead to a better understanding of the mechanisms behind neurogenesis, and the failure of the regenerative response in mammals, first of all, the role of inflammation, considered the main inhibitor of the neuronal regeneration.