Autism, heparan sulfate and potential interventions

Alexander, Jacob S; Keles, Gizem; Killingsworth, Jessica; Bronson, Ronald; Pérez, Christine; Sawmiller, Darrell; Shytle, R. Douglas

doi:10.1016/j.expneurol.2022.114050

Cited by 5 publications

(4 citation statements)

References 127 publications

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“…Exploration of the proteomic signatures of TSC with IPA highlighted the activation of immune response and the positive regulation of cytokine production further confirmed by the pathway analysis of the transcriptome. Furthermore, the IPA revealed impairment in the Slit/Robo pathways and collagen biosynthesis pathways associated with epilepsy, glioma and ASD [ 3 , 31 , 46 ]. Moreover, IPA analysis of the TSC primary cultures proteome and the pathway enrichment analysis of the transcriptome predicted significant modulation of pathways involved in the immune response, ECM and regulation of mitotic cell cycle supporting the immature phenotype as well the strong neuroinflammation and alteration of brain ECM in the epileptogenic network of TSC[ 7 , 62 ].…”

Section: Discussionmentioning

confidence: 99%

Astroglial calcium signaling and homeostasis in tuberous sclerosis complex

Romagnolo,

Dematteis,

Scheper

et al. 2024

Acta Neuropathol

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Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by the development of benign tumors in various organs, including the brain, and is often accompanied by epilepsy, neurodevelopmental comorbidities including intellectual disability and autism. A key hallmark of TSC is the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway, which induces alterations in cortical development and metabolic processes in astrocytes, among other cellular functions. These changes could modulate seizure susceptibility, contributing to the progression of epilepsy and its associated comorbidities. Epilepsy is characterized by dysregulation of calcium (Ca2+) channels and intracellular Ca2+ dynamics. These factors contribute to hyperexcitability, disrupted synaptogenesis, and altered synchronization of neuronal networks, all of which contribute to seizure activity. This study investigates the intricate interplay between altered Ca2+ dynamics, mTOR pathway dysregulation, and cellular metabolism in astrocytes. The transcriptional profile of TSC patients revealed significant alterations in pathways associated with cellular respiration, ER and mitochondria, and Ca2+ regulation. TSC astrocytes exhibited lack of responsiveness to various stimuli, compromised oxygen consumption rate and reserve respiratory capacity underscoring their reduced capacity to react to environmental changes or cellular stress. Furthermore, our study revealed significant reduction of store operated calcium entry (SOCE) along with strong decrease of basal mitochondrial Ca2+ concentration and Ca2+ influx in TSC astrocytes. In addition, we observed alteration in mitochondrial membrane potential, characterized by increased depolarization in TSC astrocytes. Lastly, we provide initial evidence of structural abnormalities in mitochondria within TSC patient-derived astrocytes, suggesting a potential link between disrupted Ca2+ signaling and mitochondrial dysfunction. Our findings underscore the complexity of the relationship between Ca2+ signaling, mitochondria dynamics, apoptosis, and mTOR hyperactivation. Further exploration is required to shed light on the pathophysiology of TSC and on TSC associated neuropsychiatric disorders offering further potential avenues for therapeutic development.

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Section: Discussionmentioning

confidence: 99%

Astroglial calcium signaling and homeostasis in tuberous sclerosis complex

Romagnolo,

Dematteis,

Scheper

et al. 2024

Acta Neuropathol

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“…Examination of postmortem brain tissues from the subventricular zone of the brain lateral ventricles of young to elderly individuals with autism revealed reduced heparan sulfate immuno uorescence compared to typically developing subjects [40]. It has been suggested that heparan sulfate de ciency may lead to defective Slit/Robo signaling, and thereby affect axonal guidance and dendritic spine formation [41,42]. Moreover, subjects with ASD have lower levels of thiols such as methionine, cysteine, and glutathione [11] and sulfates [43] in their blood while urinary sulfur-containing molecules such as sulfate, sul te, and thiosulphate are increased [44].…”

Section: Discussionmentioning

confidence: 99%

Comparison of urine glycosaminoglycan excretion between children with autism spectrum disorder and typically developed children

Indika,

Jasinge,

Wijetunge

et al. 2024

Research in Autism Spectrum Disorders

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“…The physical and psychosocial disorders of ASD, added to the limitations in neuropsychomotor development, have neuroinflammatory, macrostructural and microstructural implications in the pediatric brain with autism, as reported by Alexander et al (2022). Research suggests that reduced levels of Heparan Sulfate (HS), an acidic, linear glycosaminoglycan (GAG), may be associated with autism.…”

Section: Interventionsmentioning

confidence: 99%

“…When comparing the studies, we observed that each one addresses different aspects of ASD, from specific communicative interventions to strategies based on sensory stimuli and approaches to optimizing neuropsychomotor development. While Hampton et al (2020) highlights the promising prospect of improving communication, Xu et al (2019) and Alexander et al (2022) explore physical and neurobiological interventions, respectively.…”

Section: Interventionsmentioning

confidence: 99%