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The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia.

ABSTRACT: It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.

SUBMITTER: Nehme R

PROVIDER: S-EPMC9237031 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia.

Nehme Ralda R Pietiläinen Olli O Artomov Mykyta M Tegtmeyer Matthew M Valakh Vera V Lehtonen Leevi L Bell Christina C Singh Tarjinder T Trehan Aditi A Sherwood John J Manning Danielle D Peirent Emily E Malik Rhea R Guss Ellen J EJ Hawes Derek D Beccard Amanda A Bara Anne M AM Hazelbaker Dane Z DZ Zuccaro Emanuela E Genovese Giulio G Loboda Alexander A AA Neumann Anna A Lilliehook Christina C Kuismin Outi O Hamalainen Eija E Kurki Mitja M Hultman Christina M CM Kähler Anna K AK Paulo Joao A JA Ganna Andrea A Madison Jon J Cohen Bruce B McPhie Donna D Adolfsson Rolf R Perlis Roy R Dolmetsch Ricardo R Farhi Samouil S McCarroll Steven S Hyman Steven S Neale Ben B Barrett Lindy E LE Harper Wade W Palotie Aarno A Daly Mark M Eggan Kevin K

Nature communications 20220627 1

It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered t ...[more]

PMID: 35760976

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Project description:TSNARE1, which encodes the protein tSNARE1, is a high-confidence gene candidate for schizophrenia risk, but nothing is known about its cellular or physiological function. We identified the major gene products of TSNARE1 and their cytoplasmic localization and function in endosomal trafficking in cortical neurons. We validated three primary isoforms of TSNARE1 expressed in human brain, all of which encode a syntaxin-like Qa SNARE domain. RNA-sequencing data from adult and fetal human brain suggested that the majority of tSNARE1 lacks a transmembrane domain that is thought to be necessary for membrane fusion. Biochemical data demonstrate that tSNARE1 can compete with Stx12 for incorporation into an endosomal SNARE complex, supporting its possible role as an inhibitory SNARE. Live-cell imaging in cortical neurons from mice of both sexes demonstrated that brain tSNARE1 isoforms localized to the endosomal network. The most abundant brain isoform, tSNARE1c, localized most frequently to Rab7+ late endosomes, and endogenous tSNARE1 displayed a similar localization in human neural progenitor cells and neuroblastoma cells. In mature rat neurons from both sexes, tSNARE1 localized to the dendritic shaft and dendritic spines, supporting a role for tSNARE1 at the postsynapse. Expression of either tSNARE1b or tSNARE1c, which differ only in their inclusion or exclusion of an Myb-like domain, delayed the trafficking of the dendritic endosomal cargo Nsg1 into late endosomal and lysosomal compartments. These data suggest that tSNARE1 regulates endosomal trafficking in cortical neurons, likely by negatively regulating early endosomal to late endosomal trafficking.SIGNIFICANCE STATEMENT Schizophrenia is a severe and polygenic neuropsychiatric disorder. Understanding the functions of high-confidence candidate genes is critical toward understanding how their dysfunction contributes to schizophrenia pathogenesis. TSNARE1 is one of the high-confidence candidate genes for schizophrenia risk, yet nothing was known about its cellular or physiological function. Here we describe the major isoforms of TSNARE1 and their cytoplasmic localization and function in the endosomal network in cortical neurons. Our results are consistent with the hypothesis that the majority of brain tSNARE1 acts as a negative regulator to endolysosomal trafficking.

Dataset Information

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia.

Publications

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia.

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