Microexons: at the nexus of nervous system development, behaviour and autism spectrum disorder

Current Opinion in Genetics & Development, Год журнала: 2020, Номер 65, С. 22 - 33

Опубликована: Июнь 11, 2020

Язык: Английский

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Altered dopaminergic pathways and therapeutic effects of intranasal dopamine in two distinct mouse models of autism

Molecular Brain, Год журнала: 2020, Номер 13(1)

Опубликована: Авг. 10, 2020

The dopamine (DA) system has a profound impact on reward-motivated behavior and is critically involved in neurodevelopmental disorders, such as autism spectrum disorder (ASD). Although DA defects are found autistic patients, it not well defined how the pathways altered ASD whether can be utilized potential therapeutic agent for ASD. To this end, we employed phenotypic genetic model, i.e., Black Tan BRachyury T+Itpr3tf/J (BTBR) mice Fragile X Mental Retardation 1 knockout (Fmr1-KO) mice, respectively. Immunostaining of tyrosine hydroxylase (TH) to mark dopaminergic neurons revealed an overall reduction TH expression substantia nigra, ventral tegmental area dorsal striatum BTBR compared C57BL/6 J wild-type ones. In contrast, Fmr1-KO animals did show alteration but displayed abnormal morphology TH-positive axons with higher "complexity" lower "texture". Both strains exhibited decreased striatal transporter (DAT) increased spatial coupling between vesicular glutamate (VGLUT1, label glutamatergic terminals) signals, while GABAergic quantified by glutamic acid decarboxylase 67 (GAD67) remained intact. Intranasal administration rescued deficits non-selective attention, object-based attention social approaching likely enhancing level striatum. Application intranasal alleviated their impairment novelty, association reduced protein. These results suggest that although modified differently two models, treatment effectively rectifies behavioral phenotypes, which may present promising therapy diverse types

Язык: Английский

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FMRP regulates mRNAs encoding distinct functions in the cell body and dendrites of CA1 pyramidal neurons

eLife, Год журнала: 2021, Номер 10

Опубликована: Дек. 23, 2021

Neurons rely on translation of synaptic mRNAs in order to generate activity-dependent changes plasticity. Here, we develop a strategy combining compartment-specific crosslinking immunoprecipitation (CLIP) and translating ribosome affinity purification (TRAP) conditionally tagged mice precisely define the ribosome-bound dendritic transcriptome CA1 pyramidal neurons. We identify transcripts with differentially localized mRNA isoforms generated by alternative polyadenylation splicing, including many that have altered protein-coding capacity. Among mRNAs, FMRP targets were found be overrepresented. Cell-type-specific FMRP-CLIP TRAP microdissected neuropil revealed 383 suggests regulates functionally distinct modules dendrites cell bodies. ~15-20% encoding functions 10% chromatin modulators, dendrite body, respectively. In absence FMRP, had increased association, consistent function for translational repression. Conversely, downregulation involved regulation bodies role stabilizing containing stalled ribosomes this compartment. Together, data support model which expression nuclear proteins within different compartments single neuronal type.

Язык: Английский

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RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(21), С. 11870 - 11870

Опубликована: Ноя. 1, 2021

The intrinsic cellular heterogeneity and molecular complexity of the mammalian nervous system relies substantially on dynamic nature spatiotemporal patterning gene expression. These features expression are achieved in part through mechanisms involving various epigenetic processes such as DNA methylation, post-translational histone modifications, non-coding RNA activity, amongst others. In concert, another regulatory layer by which bases sugar residues chemically modified enhances neuronal transcriptome complexity. Similar modifications other systems collectively constitute epitranscriptome that integrates impacts physiological processes. is reshaped constantly to regulate vital development, differentiation stress responses. Perturbations can lead pathogenic conditions, including cancer, cardiovascular abnormalities neurological diseases. Recent advances next-generation sequencing technologies have enabled us identify locate bases/sugars different species. modulate stability, transport and, most importantly, translation RNA. this review, we discuss formation functions some frequently observed modifications—including methylations adenine cytosine bases, isomerization uridine pseudouridine—at layers metabolism, together with their contributions abnormal conditions neurodevelopmental disorders.

Язык: Английский

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FMR1 and Autism, an Intriguing Connection Revisited

Genes, Год журнала: 2021, Номер 12(8), С. 1218 - 1218

Опубликована: Авг. 6, 2021

Autism Spectrum Disorder (ASD) represents a distinct phenotype of behavioral dysfunction that includes deficiencies in communication and stereotypic behaviors. ASD affects about 2% the US population. It is highly heritable spectrum conditions with substantial genetic heterogeneity. To date, mutations over 100 genes have been reported association phenotypes. Fragile X syndrome (FXS) most common single-gene disorder associated ASD. The gene FXS, FMR1 located on chromosome X. Accordingly, condition has more severe manifestations males. FXS results from loss function due to expansion an unstable CGG repeat 5'' untranslated region gene. About 50% males 20% females meet Diagnostic Statistical Manual 5 (DSM-5) criteria for Among individuals ASD, 3% test positive FXS. FMRP, protein product FMR1, major regulator central nervous system. Multiple pathways regulated by FMRP are found be dysfunctional patients who do not Thus, presents opportunity study cellular phenomena may wider applications management develop new strategies therapy.

Язык: Английский

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