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Impaired aggrephagy,abnormal vesicular trafficking and cellular stress, lead to protein aggregation,neurodegeneration and synaptic dysfunction in cerebellar vermis of children and adults with idiopathic autism

ABSTRACT: Autism spectrum disorder (ASD) is a debilitating neurodevelopmental disorder with genetic and environmental etiologies involving several brain areas exhibiting abnormalities of cognition and social behavior. Previous work showed involvement of synaptic abnormalities in dorsolateral prefrontal cortex. We hypothesized whether similar synaptic proteins were involved in pathology of cerebellar vermis of children and adults with ASD. Subcellular fractions of synaptosomes from cerebellar vermal cortices of age-, brain area-, and postmortem-interval- matched samples from children and adults with idiopathic ASD vs. controls were subjected to HPLC-tandem mass spectrometry. Analysis of proteomic data in cerebellar vermis showed common and distinct effects of ASD on protein- and pathway-enrichment for children vs. adults.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Synapse

DISEASE(S): Autism Spectrum Disorder

SUBMITTER: Arthur Eschenlauer

LAB HEAD: S Hossein Fatemi

PROVIDER: PXD061746 | Pride | 2025-08-25

REPOSITORIES: Pride

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	fatem002_18132_20210728_TMT10_Child.mzML	Mzml
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Publications

Impaired Aggrephagy, Interrupted Vesicular Trafficking, and Cellular Stress, Lead to Protein Aggregation, and Synaptic Dysfunction in Cerebellum of Children and Adults with Idiopathic Autism.

Fatemi S Hossein SH Folsom Timothy D TD Eschenlauer Arthur A Chekouo Thierry T

Cerebellum (London, England) 20250808 5

PMID: 40779003

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Quantitative Proteomics of Dorsolateral Prefrontal Cortex

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Autism-associated gene expression signatures in peripheral blood leucocytes

Project description:Using DNA microarray as a global approach to understanding the molecular basis of autism, we examined gene expression profiling in peripheral blood from 21 young adults with autism spectrum disorder (ASD) and healthy mothers having children with ASD, between whom there was no blood relationship. Several genes which were significantly changed in the ASD group comparing with their age- and gender-matched healthy subjects were mainly involved in cell morphology, cellular assembly and organization, and nerve system development and function. In addition, mothers having children with ASD possessed a unique gene expression signature shown as significant alterations of protein synthesis despite of their nonautistic diagnostic status. Moreover, an ASD-associated gene expression signature was commonly observed in both individuals with ASD and healthy mothers having children with ASD. Total RNA was prepared from venous blood which was taken from each subject. Gene expression profiling of venous blood from subjects with ASD (21), the healthy women who had children with ASD (21) and their age- and gender-matched healthy subjects (42) were obtained using a whole human genome oligonucleotide microarray (Agilent 44K Human whole genome array G4112F, GPL6480) to measure gene expression in these samples according to the manufacture’s protocol. The one GSM sample of microarray analysis was made by individual subject. Differentially expressed genes were determined across all rationed expression values for age- and gender-matched pairs (ASD vs. control, asdMO vs. ctrlMO) using Genespling analysis.

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Project description:The molecular etiology of numerous risk genes for autism spectrum disorder (ASD), including CDH11, remains elusive. We investigated the role of CDH11 in the development of ASD-related behaviors using gene-deficient mice. CDH11 is enriched at synapses in glutamatergic neurons of the anterior cingulate cortex (ACC), which project to the striatum, nucleus accumbens, and amygdala. Ablation of Cdh11 in these neurons during development increases self-grooming and reduces sociability, with decreased neuronal activity in the ACC. Chemogenetic inhibition of ACC glutamatergic neurons recapitulates the over-grooming phenotype, while activation of these neurons mitigates self-grooming in Cdh11-deficient mice. Proteomics of ACC synaptosomes and CDH11 interactomes suggest the involvement of CDH11 in synaptic vesicle trafficking, supported by reduced presynaptic vesicle density at excitatory synapses in Cdh11-deficient mice. These findings highlight the critical role of CDH11 in ASD-related brain circuit development and offer insights into the molecular mechanisms and potential therapeutic targets for ASD.

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A Pilot Proteomic Study of Protein Markers in Autism Spectrum Disorder

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2022-02-22 | PXD000679 | Pride

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