Genetic Variation in Imprinted Genes is Associated with Risk of Late-Onset Alzheimer's Disease

Chaudhry, Mamoonah; Wang, Xingbin; Bamne, Mikhil; Hasnain, Shahida; Demirci, F. Yesim; López, Oscar L.; Kamboh, M. Ilyas

doi:10.3233/jad-142106

Cited by 36 publications

(21 citation statements)

References 32 publications

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“…differentiation could replace lost or damaged neurons that result from Ab plaque and is therefore helpful for improving cognitive dysfunction by establishing new synaptic connectivity (46). Of interest, GPR1 in the brain is a candidate marker for AD as suggested by a gene-based analysis (47). As it is maternally imprinted, GPR1 may provide a mechanism for the higher maternal inheritance in patients with AD (48); therefore, FAM19A1 and its receptor, GPR1, might be associated with neural disorders and neurodegenerative diseases by modulating the functions of NSCs.…”

Section: Discussionmentioning

confidence: 99%

FAM19A1 is a new ligand for GPR1 that modulates neural stem‐cell proliferation and differentiation

et al. 2018

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FAM19A1 is a member of the family with sequence similarity 19 with unknown function. FAM19A1 mRNA expression is restricted to the CNS. Here, we report that FAM19A1 is a classic secretory protein, and expression levels correlate with brain development, increasing from embryonic d 12.5, peaking between postnatal d (P)1 and P7 and decreasing at wk 8. The adult hippocampus is a region of FAM19A1 high expression. Recombinant FAM19A1 suppressed the proliferation and self-renewal of neural stem cells (NSCs) and altered the lineage progression of NSCs with promoted neuron differentiation and suppressed astrocyte differentiation. Although GPCR 1 (GPR1) has been reported to be expressed in the CNS, its functions in the brain remain unclear. We identified GPR1 to be a functional receptor for FAM19A1. FAM19A1 interacted with GPR1 via the N-terminal domain (GPR1-ND), and its NSC modulatory functions required the Rho-associated protein kinase (ROCK) /ERK1/2 and ROCK/signal transducer and activator of transcription 3 signaling pathways. GPR1-ND that selectively bound to FAM19A1 neutralized the effects of FAM19A1 on NSC functions. Taken together, our results show, for the first time to our knowledge, that FAM19A1 is a novel regulatory factor of the proliferation and differentiation of NSCs, and identified a novel mechanism by which GPCR mediates the effects of FAM19A1 on NSC functions that may be important for brain development and neurogenesis. Additional exploration of the functions of FAM19A1 and GPR1 in the CNS may broaden the range of therapeutic options available for major brain disorders.-Zheng, C., Chen, D., Zhang, Y., Bai, Y., Huang, S., Zheng, D., Liang, W., She, S., Peng, X., Wang, P., Mo, X., Song, Q., Lv, P., Huang, J., Ye, R. D., Wang, Y. FAM19A1 is a new ligand for GPR1 that modulates neural stem-cell proliferation and differentiation.

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Section: Discussionmentioning

confidence: 99%

FAM19A1 is a new ligand for GPR1 that modulates neural stem‐cell proliferation and differentiation

et al. 2018

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“…We note that at least seven of our nutrition-sensitive G1 DMRs are in close spatial proximity to imprinted genes, including: IGF1R insulin growth factor1 receptor 1 (53); KCNQ1DN and WT1 important for Wilms tumor biology (54) and ( WT1 ) implicated in neurodegenerative disease(55); the MEST and MESTIT1 genes as maternal stress-sensitive genes regulating parental behaviors and body mass in offspring(56); and SLC22A18AS and VTRNA2-1 which have not yet been explored in the nervous system. Such epigenetic dysregulation—with an impressive >40-fold overrepresentation of methyl-CpG changes for imprinted loci in the present study— could affect not only the risk exposed G1 subjects but also the earliest stages of development in their offspring, even in the absence of an intergenerational transmission of the G1-specific DNA methylation changes.…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition

Peter

Fischer

Kundaković

et al. 2016

Biological Psychiatry

126

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Background Early childhood malnutrition affects 113 million children worldwide, impacting health and increasing vulnerability for cognitive and behavioral disorders later in life. Molecular signatures after childhood malnutrition, including the potential for intergenerational transmission, remain unexplored. Methods We surveyed blood DNA methylomes (~483,000 individual CpG sites) in 168 subjects across two generations (G1,G2), including 50 G1 individuals hospitalized during the first year of life for moderate to severe protein energy malnutrition, then followed up to 48 years in the Barbados Nutrition Study. Attention deficits and cognitive performance were evaluated with Connors Adult Attention Rating Scale (CAARS) and Wechsler Abbreviated Scale of Intelligence (WASI). Expression of nutrition-sensitive genes was explored by qRT-PCR in rat prefrontal cortex. Results We identified altogether 134 nutrition-sensitive differentially methylated genomic regions (DMR), with the overwhelming majority (87%) specific for G1. Multiple neuropsychiatric risk genes, including COMT, IFNG, MIR200B, SYNGAP1 and VIP2R showed associations of specific methyl-CpGs with attention and IQ. Interferon Gamma (IFNG) expression was decreased in prefrontal cortex of rats showing attention deficits after developmental malnutrition. Conclusions Early childhood malnutrition entails long lasting epigenetic signatures associated with liability for attention and cognition, and limited potential for intergenerational transmission.

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“…The Dlgap2 -/- mice have reduced spine density in the orbitofrontal cortex accompanied with downregulation of synaptic proteins, Homer1 and αCaMKII, as well as receptors, NR1 and GluR1, and exhibit exacerbated aggressive behaviors (Jiang-Xie et al, 2014). Molecular and genetic studies have demonstrated that alterations in DLGAP2 are involved the pathophysiology of various psychiatric conditions, including schizophrenia, Alzheimer’s disease, post-tramautic syndrome, and pediatric obsessive-compulsive disorder (Chertkow-Deutsher et al, 2010; Wu et al, 2013; Li et al, 2014b; Chaudhry et al, 2015). Rare de novo CNVs, deletions, and duplications of DLGAP2 have been reported in individuals with ASD, but how mutations of DLGAP2 contribute to autism is still largely unknown (Marshall et al, 2008; Ozgen et al, 2009; Chien et al, 2010; Pinto et al, 2010; Cukier et al, 2014).…”

Section: Synaptic Proteins Regulate Synaptic Function To Maintain Neumentioning

confidence: 99%

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.

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Genetic Variation in Imprinted Genes is Associated with Risk of Late-Onset Alzheimer's Disease

Cited by 36 publications

References 32 publications

FAM19A1 is a new ligand for GPR1 that modulates neural stem‐cell proliferation and differentiation

FAM19A1 is a new ligand for GPR1 that modulates neural stem‐cell proliferation and differentiation

DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

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