The DPYSL2 gene connects mTOR and schizophrenia

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• A polymorphic CT di-nucleotide repeat (DNR) in the 5'-untranslated region (UTR) of the DPYSL2 gene is associated with schizophrenia.
• This DNR exhibits allelic differences in response to mammalian target of Rapamycin (mTOR) signaling.

Purpose of the Study:

• To investigate the functional impact of the DPYSL2 DNR and its interaction with mTOR signaling in the context of schizophrenia.
• To explore the downstream molecular effects of the schizophrenia risk variant of the DPYSL2 DNR.

Main Methods:

• Microarray analysis to identify protein interactions with DNR alleles.
• Electrophoretic mobility shift assays to confirm protein binding.
• CRISPR/Cas9 gene editing to introduce the schizophrenia risk variant (13DNR).
• RNA sequencing (RNA-seq) to analyze transcriptome changes in edited cells.

Main Results:

• Differential interaction of DNR alleles with mTOR-related proteins, including HuD/ELAVL4.
• CRISPR/Cas9-edited cells with the 13DNR variant showed reduced CRMP2 isoform levels and twofold shorter cellular projections.
• RNA-seq revealed significant transcriptome alterations in edited cells, enriched in immunity-related genes.
• These gene expression changes showed overlap with ZNF804A targets and reversed signatures of antipsychotic drug treatment.

Conclusions:

• The DPYSL2 DNR is functionally important and plays a role in schizophrenia pathogenesis.
• mTOR signaling is implicated in the molecular mechanisms underlying schizophrenia through its interaction with the DPYSL2 DNR.