The Ubiquitin System: a Regulatory Hub for Intellectual Disability and Autism Spectrum Disorder

Kasherman, Maria; Premarathne, Susitha; Wood, Stephen A.; Piper, Michael

doi:10.1007/s12035-020-01881-x

Cited by 26 publications

(34 citation statements)

References 174 publications

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“…Both signaling pathways are not only important for early normal brain development but also for neurogenesis in the adult brain 47 . mTOR has been suggested to regulate neuronal differentiation and dendritic maturation 48 . Canonical Wnt-signaling has a major role in neurogenesis.…”

Section: Biological Pathways and Their Link With Adhdmentioning

confidence: 99%

“…Dysregulation of both pathways may lead to pathological brain developmental conditions. For example, Kasherman and colleagues 48 have shown how abnormalities in the ubiquitin system, a major regulator of key signaling cascades including mTOR and Wnt, are linked to two common neurodevelopmental disorders: intellectual disability (ID) and ASD.…”

Section: Biological Pathways and Their Link With Adhdmentioning

confidence: 99%

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The stress–Wnt-signaling axis: a hypothesis for attention-deficit hyperactivity disorder and therapy approaches

et al. 2020

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Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric neurodevelopmental disorders in children and adolescents. Although ADHD has been studied for nearly a century, the cause and pathophysiology of ADHD is yet largely unknown. However, findings from previous studies have resulted in the formation of a new hypothesis: Apart from the well-known multifactorial etiology of ADHD, recent evidence suggests that the interaction between genetic and environmental factors and especially Wnt- and mTOR-signaling pathways might have an important role in the pathophysiology of ADHD. The Wnt-signaling pathway is known to orchestrate cellular proliferation, polarity, and differentiation, and the mTOR pathway is involved in several significant processes of neurodevelopment and synaptic plasticity. As a result, dysregulations of these pathways in a time-dependent manner could lead to neurodevelopmental delays, resulting in ADHD phenotype. This review presents further evidence supporting our hypothesis by combining results from studies on ADHD and Wnt- or mTOR-signaling and the influence of genetics, methylphenidate treatment, Omega-3 supplementation, and stress.

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Section: Biological Pathways and Their Link With Adhdmentioning

confidence: 99%

Section: Biological Pathways and Their Link With Adhdmentioning

confidence: 99%

The stress–Wnt-signaling axis: a hypothesis for attention-deficit hyperactivity disorder and therapy approaches

et al. 2020

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“…Therefore, rather than investigating individual genes and the multiple pathways they may regulate, it would be more feasible to find network hubs of genes that have common pathways in abnormal developmental mechanisms leading to intellectual disability. Recently, the gene, ubiquitin specific protease 9 X-linked (USP9X), has been suggested to be a hub for regulating various factors involved in intellectual disability (Johnson et al, 2020;Kasherman et al, 2020). USP9X, a deubiquitylating enzyme, has been shown to regulate NSC proliferation and neuronal maturation (Jolly et al, 2009;Oishi et al, 2016).…”

Section: Malformations Of Cortical Developmentmentioning

confidence: 99%

“…Intellectual disability has been implicated in over 500 genes and 900 developmental disorders (Chiurazzi & Pirozzi, 2016;Gilissen et al, 2014;Grozeva et al, 2015). Recently, the ubiquitin system has been suggested to act as an interactome hub for autism spectrum disorder (ASD) and intellectual disability (Kasherman et al, 2020). One member of the ubiquitin system called ubiquitin specific protease 9 X-linked (USP9X), has been shown to regulate multiple key signalling pathways involved in the etiology of ASD and intellectual disability, including the mammalian target of rapamycin (mTOR), transforming growth factor  (TGF)bone morphogenetic protein (BMP) and wigless (WNT) pathways (Kasherman et al, 2020;Murtaza et al, 2015).…”

Section: Usp9x Mutations Causes Intellectual Disability In Humansmentioning

confidence: 99%

“…Recently, the ubiquitin system has been suggested to act as an interactome hub for autism spectrum disorder (ASD) and intellectual disability (Kasherman et al, 2020). One member of the ubiquitin system called ubiquitin specific protease 9 X-linked (USP9X), has been shown to regulate multiple key signalling pathways involved in the etiology of ASD and intellectual disability, including the mammalian target of rapamycin (mTOR), transforming growth factor  (TGF)bone morphogenetic protein (BMP) and wigless (WNT) pathways (Kasherman et al, 2020;Murtaza et al, 2015). Humans with USP9X mutations exhibit cortical malformations, such as intellectual disability, ASD, as well as structural brain abnormalities including thin corpus callosum and cerebellar defects.…”

Section: Usp9x Mutations Causes Intellectual Disability In Humansmentioning

confidence: 99%

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Molecular mechanisms underlying malformations of cortical development

Oishi¹

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Nuclear Factor One X (NFIX) haploinsufficiency in humans results in Malan syndrome, a disorder characterized by overgrowth, macrocephaly and intellectual disability. Although clinical assessments have determined the underlying symptomology of Malan syndrome, the fundamental mechanisms contributing to the enlarged head circumference and intellectual disability in these patients remains undefined. Here, we used Nfix heterozygous mice as a model to investigate these aspects of Malan syndrome. Volumetric magnetic resonance imaging (MRI) was used to calculate the volumes of 20 brain sub regions. Diffusion tensor MRI was used to perform tractography-based analyses of the corpus callosum, hippocampal commissure, and anterior commissure, as well as structural connectome mapping of the whole brain. Immunohistochemistry examined the neocortical cellular populations. Two behavioural assays were performed, including the active place avoidance task to assess spatial navigation and learning and memory function, and the 3-chambered sociability task to examine social behaviour. Adult Nfix+/-mice exhibit significantly increased brain volume (megalencephaly) compared to wildtypes, with the cerebral cortex showing the highest increase. Moreover, all three forebrain commissures, in particular the anterior commissure, revealed significantly reduced fractional anisotropy, axial and radial diffusivity, and tract density intensity. Structural connectome analyses revealed aberrant connectivity between many crucial brain regions. Finally, Nfix+/-mice exhibit behavioural deficits that model intellectual disability. Collectively, these data provide a significant conceptual advance in our understanding of Malan syndrome by suggesting that megalencephaly underlies the enlarged head size of these patients, and that disrupted cortical connectivity may contribute to the intellectual disability these patients exhibit.

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Ribosome‐associated quality control mediates degradation of the premature translation termination product Orf1p of ODC antizyme mRNA

et al. 2021

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Decoding of OAZ1 (Ornithine decarboxylase AntiZyme 1) mRNA, which harbours two open reading frames (ORF1 and ORF2) interrupted by a naturally occurring Premature Termination Codon (PTC), produces an 8 kDa truncated polypeptide termed Orf1p, unless the PTC is bypassed by +1 ribosomal frameshifting. In this study, we identified Orf1p as an endogenous ubiquitin‐dependent substrate of the 26S proteasome both in yeast and mammalian cells. Surprisingly, we found that the ribosome‐associated quality control factor Rqc1 and the ubiquitin ligase Ltn1 are critical for Orf1p degradation. In addition, the cytosolic protein quality control chaperone system Hsp70/Hsp90 and their corresponding co‐chaperones Sse1, Fes1, Sti1 and Cpr7 are also required for Orf1p proteolysis. Our study finds that Orf1p, which is naturally synthesized as a result of a premature translation termination event, requires the coordinated role of both ribosome‐associated and cytosolic protein quality control factors for its degradation.

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The Ubiquitin System: a Regulatory Hub for Intellectual Disability and Autism Spectrum Disorder

Cited by 26 publications

References 174 publications

The stress–Wnt-signaling axis: a hypothesis for attention-deficit hyperactivity disorder and therapy approaches

The stress–Wnt-signaling axis: a hypothesis for attention-deficit hyperactivity disorder and therapy approaches

Molecular mechanisms underlying malformations of cortical development

Ribosome‐associated quality control mediates degradation of the premature translation termination product Orf1p of ODC antizyme mRNA

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