Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease-relevant pathologies

Murtaza, Nadeem; Cheng, Annie A.; Brown, Chad O; Meka, Durga Praveen; Hong, Shuai; Uy, Jarryll; El-Hajjar, Joelle; Pipko, Neta; Unda, Brianna K.; Schwanke, Birgit; Xing, Sansi; Thiruvahindrapuram, Bhooma; Engchuan, Worrawat; Trost, Brett; Deneault, Éric; Anda, Froylán Calderón de; Doble, Bradley W.; Ellis, James; Anagnostou, Evdokia; Bader, Gary D.; Scherer, Stephen W.; Lu, Yu; Singh, Karun K.

doi:10.1016/j.celrep.2022.111678

Cited by 26 publications

(27 citation statements)

References 149 publications

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“…Consistently with the major role of DPYSL proteins in dendritic organization and in formation and maturation of synapse, various studies suggested that they would contribute in the pathophysiology of psychiatric diseases such as schizophrenia and NDDs ( Table 3 ; Edgar et al, 2000 ; Charrier et al, 2003 ; Hong et al, 2005 ; Beasley et al, 2006 ; Bader et al, 2012 ; Braunschweig et al, 2013 ; Yamashita et al, 2013 ; Lee et al, 2015 ; Quach et al, 2015 ; Tsutiya et al, 2017 ; Quach et al, 2021 ; Murtaza et al, 2022 ) (database SFARI, denovo-db). Interestingly, dendritic and spine dysfunctions are described in NDDs including schizophrenia, Down’s syndrome, Fragile X syndrome, Rett syndrome and ASD ( Huttenlocher, 1991 ; Kaufmann and Moser, 2000 ; Martínez-Cerdeño, 2017 ; Nelson and Bender, 2021 ; Quach et al, 2021 ).…”

Section: Dpysl Genes and Neurodevelopmental Disordersmentioning

confidence: 69%

Contribution of the dihydropyrimidinase-like proteins family in synaptic physiology and in neurodevelopmental disorders

et al. 2023

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The dihydropyrimidinase-like (DPYSL) proteins, also designated as the collapsin response mediators (CRMP) proteins, constitute a family of five cytosolic phosphoproteins abundantly expressed in the developing nervous system but down-regulated in the adult mouse brain. The DPYSL proteins were initially identified as effectors of semaphorin 3A (Sema3A) signaling and consequently involved in regulation of growth cone collapse in young developing neurons. To date, it has been established that DPYSL proteins mediate signals for numerous intracellular/extracellular pathways and play major roles in variety of cellular process including cell migration, neurite extension, axonal guidance, dendritic spine development and synaptic plasticity through their phosphorylation status. The roles of DPYSL proteins at early stages of brain development have been described in the past years, particularly for DPYSL2 and DPYSL5 proteins. The recent characterization of pathogenic genetic variants in DPYSL2 and in DPYSL5 human genes associated with intellectual disability and brain malformations, such as agenesis of the corpus callosum and cerebellar dysplasia, highlighted the pivotal role of these actors in the fundamental processes of brain formation and organization. In this review, we sought to establish a detailed update on the knowledge regarding the functions of DPYSL genes and proteins in brain and to highlight their involvement in synaptic processing in later stages of neurodevelopment, as well as their particular contribution in human neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASD) and intellectual disability (ID).

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Section: Dpysl Genes and Neurodevelopmental Disordersmentioning

confidence: 69%

Contribution of the dihydropyrimidinase-like proteins family in synaptic physiology and in neurodevelopmental disorders

et al. 2023

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“…Indeed, ∼90% of the >1,000 identified interactions are novel, potentially because most previous protein interaction studies were performed in non-neural cell lines or tissues. This work, along with data probing the PPI of ASD risk genes in mouse cortical neurons, 6 demonstrates that most neurally relevant PPIs may be unknown. The authors uncover genes within the network that have not been implicated in disease and identify novel interactions of specific isoforms related to relevant disease pathways.…”

Section: Main Textmentioning

confidence: 88%

“…The expression of known ASD risk genes is concentrated in, but not exclusive to, excitatory neurons and the timing of expression peaks during fetal brain development. 3 , 4 While genomics and transcriptomics have led to understanding the underlying biology of genetic risk for ASD in general, with exceptions, 5 , 6 , 7 few studies have tackled proteomics in a neuronal cell framework.…”

Section: Main Textmentioning

confidence: 99%

Neuronal protein interaction networks in autism spectrum disorder

2023

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“…Human fibroblasts from individuals with Williams syndrome (i.e., hemizygous for DNAJC30) were also found to have impaired mitochondrial function and reduced ATP production (34). In addition, a recent study of reciprocal CNVs at the neurodevelopmental disorder-associated locus 16p11.2 also found a strong signal for enrichment of DEGs related to energy metabolism and mitochondrial function in both mouse brain and cultured human neural cell lines (35), and loss of the 16p11.2 locus-encoded gene TAOK2 was found to disrupt mitochondrial morphology and function in mouse neurons (36). Another study of convergent biology in mouse models of the neurodevelopmental CNVs 1q21.1, 15q13.3, and 22q11.2 found dysregulation of a transcriptomic module related to neuronal energetics (37).…”

Section: Discussionmentioning

confidence: 99%

Cross-species analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion

Purcell,

Sefik,

Werner

et al. 2023

Sci. Adv.

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The 1.6-megabase deletion at chromosome 3q29 (3q29Del) is the strongest identified genetic risk factor for schizophrenia, but the effects of this variant on neurodevelopment are not well understood. We interrogated the developing neural transcriptome in two experimental model systems with complementary advantages: isogenic human cortical organoids and isocortex from the 3q29Del mouse model. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 and 12 months, as well as perinatal mouse isocortex, all at single-cell resolution. Systematic pathway analysis implicated dysregulation of mitochondrial function and energy metabolism. These molecular signatures were supported by analysis of oxidative phosphorylation protein complex expression in mouse brain and assays of mitochondrial function in engineered cell lines, which revealed a lack of metabolic flexibility and a contribution of the 3q29 gene PAK2. Together, these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species.

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Neuron-specific protein network mapping of autism risk genes identifies shared biological mechanisms and disease-relevant pathologies

Cited by 26 publications

References 149 publications

Contribution of the dihydropyrimidinase-like proteins family in synaptic physiology and in neurodevelopmental disorders

Contribution of the dihydropyrimidinase-like proteins family in synaptic physiology and in neurodevelopmental disorders

Neuronal protein interaction networks in autism spectrum disorder

Cross-species analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion

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