Understanding Abnormal SMO-SHH Signaling in Autism Spectrum Disorder: Potential Drug Target and Therapeutic Goals

Rahi, Saloni; Mehan, Sidharth

doi:10.1007/s10571-020-01010-1

Cited by 23 publications

(22 citation statements)

References 181 publications

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“…Disruptions in their proper functioning and interactions can contribute to neurodevelopmental disorders, including ASD. Numerous therapeutic interventions, targeting different elements of their signaling pathways and their regulation are already in trial or use for the treatment of several neurological diseases (Baranova et al., 2020; Rahi & Mehan, 2020). While modulation of the Wnt‐β‐catenin and Shh pathways may offer potential therapeutic benefit in the management or the prevention of ASD symptoms, they require a better understanding of their crosstalk during neurovascular and neurological development, as well as time and spatial fine‐tuning.…”

Section: Discussionmentioning

confidence: 99%

“…BBB dysfunction can also potentially result from genetic abnormalities during development. For instance, recent studies have shown that alterations in the Sonic Hedgehog (Shh) and WNT / β‐catenin signaling pathways during development can result in a dysfunctional BBB, leakage of blood toxic components into the CNS, cellular infiltration, defective clearance of molecules, cerebral blood flow reduction and dysregulation, neurological deficits and may be associated with ASD pathogenesis (Alvarez et al., 2011; Liu et al., 2018; Rahi & Mehan, 2020; Stenman et al., 2008). Furthermore, although multiple Shh/Wnt and β‐catenin pathway gene mutations have been identified as ASD‐associated mutations, the role of Shh/Wnt signaling‐induced cerebrovascular deficits in ASD pathogenesis has not been elucidated (Caracci et al., 2016; Zhang et al., 2012).…”

Section: Introductionmentioning

confidence: 99%

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Potential crosstalk between sonic hedgehog‐WNT signaling and neurovascular molecules: Implications for blood–brain barrier integrity in autism spectrum disorder

Gozal

Jagadapillai

Cai

et al. 2021

Journal of Neurochemistry

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Autism Spectrum Disorder (ASD) is a neurodevelopmental disease originating from combined genetic and environmental factors. Post‐mortem human studies and some animal ASD models have shown brain neuroinflammation, oxidative stress, and changes in blood–brain barrier (BBB) integrity. However, the signaling pathways leading to these inflammatory findings and vascular alterations are currently unclear. The BBB plays a critical role in controlling brain homeostasis and immune response. Its dysfunction can result from developmental genetic abnormalities or neuroinflammatory processes. In this review, we explore the role of the Sonic Hedgehog/Wingless‐related integration site (Shh/Wnt) pathways in neurodevelopment, neuroinflammation, and BBB development. The balance between Wnt‐β‐catenin and Shh pathways controls angiogenesis, barriergenesis, neurodevelopment, central nervous system (CNS) morphogenesis, and neuronal guidance. These interactions are critical to maintain BBB function in the mature CNS to prevent the influx of pathogens and inflammatory cells. Genetic mutations of key components of these pathways have been identified in ASD patients and animal models, which correlate with the severity of ASD symptoms. Disruption of the Shh/Wnt crosstalk may therefore compromise BBB development and function. In turn, impaired Shh signaling and glial activation may cause neuroinflammation that could disrupt the BBB. Elucidating how ASD‐related mutations of Shh/Wnt signaling could cause BBB leaks and neuroinflammation will contribute to our understanding of the role of their interactions in ASD pathophysiology. These observations may provide novel targeted therapeutic strategies to prevent or alleviate ASD symptoms while preserving normal developmental processes. Cover Image for this issue: https://doi.org/10.1111/jnc.15081

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Potential crosstalk between sonic hedgehog‐WNT signaling and neurovascular molecules: Implications for blood–brain barrier integrity in autism spectrum disorder

Gozal

Jagadapillai

Cai

et al. 2021

Journal of Neurochemistry

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“…Other neurodegeneration pathologies showing demyelination at early stage are ALS, PD, SCZ, and some pathologies with the spectrum of ASD. These are likely to provide new models in which to test remyelination agents for their ability to delay neurodegeneration by promoting remyelination [ 12 , 13 , 16 , 17 ].…”

Section: The Biological Basis Of Cns Remyelinationmentioning

confidence: 99%

“…These NSCs are committed to the oligodendrocyte (OL) lineage. They differentiate into OPCs under the control of mitogenic growth factors, such as epidermal growth factor (EGF), fibroblast growth factor (FGF), and plated-derived growth factor (PDGF), and morphogenetic factors such as Sonic Hedgehog (Shh) [ 17 , 78 , 79 , 80 ]. EGF expression can influence cortical progenitor fate choice during the neural progenitor cell (NPC) proliferative stage [ 81 , 82 ].…”

Section: The Biological Basis Of Cns Remyelinationmentioning

confidence: 99%

“…Current immunomodulatory therapies can reduce or halt disease progression, but they cannot prevent the accumulation of permanent disability consequent to demyelination of axons [ 10 , 11 ]. Other CNS pathologies classically considered strictly neurodegenerative that, however, present nerve demyelination at early stages of disease are amyotrophic lateral sclerosis (ALS) [ 12 ], schizophrenia (SCZ), [ 13 , 14 , 15 , 16 ], Alzheimer’s disease (AD), Parkinson’s disease (PD), and pathologies linked to the spectrum of autistic dysfunctions (ASD) [ 17 ]. Last but not least, brain aging and age-related dementia could potentially be delayed using remyelination agents [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

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The Current Challenges for Drug Discovery in CNS Remyelination

Balestri

Giovane

Sposato

et al. 2021

IJMS

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The myelin sheath wraps around axons, allowing saltatory currents to be transmitted along neurons. Several genetic, viral, or environmental factors can damage the central nervous system (CNS) myelin sheath during life. Unless the myelin sheath is repaired, these insults will lead to neurodegeneration. Remyelination occurs spontaneously upon myelin injury in healthy individuals but can fail in several demyelination pathologies or as a consequence of aging. Thus, pharmacological intervention that promotes CNS remyelination could have a major impact on patient’s lives by delaying or even preventing neurodegeneration. Drugs promoting CNS remyelination in animal models have been identified recently, mostly as a result of repurposing phenotypical screening campaigns that used novel oligodendrocyte cellular models. Although none of these have as yet arrived in the clinic, promising candidates are on the way. Many questions remain. Among the most relevant is the question if there is a time window when remyelination drugs should be administrated and why adult remyelination fails in many neurodegenerative pathologies. Moreover, a significant challenge in the field is how to reconstitute the oligodendrocyte/axon interaction environment representative of healthy as well as disease microenvironments in drug screening campaigns, so that drugs can be screened in the most appropriate disease-relevant conditions. Here we will provide an overview of how the field of in vitro models developed over recent years and recent biological findings about how oligodendrocytes mature after reactivation of their staminal niche. These data have posed novel questions and opened new views about how the adult brain is repaired after myelin injury and we will discuss how these new findings might change future drug screening campaigns for CNS regenerative drugs.

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