Schizophrenia-linked protein tSNARE1 regulates endolysosomal trafficking in cortical neurons

Abstract 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 endolysosomal trafficking in murine cortical neurons. We validated four 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. Live-cell imaging demonstrated that brain tSNARE1 isoforms localized to compartments of the endosomal network. The most abundant brain isoform, tSNARE1c, localized most frequently to Rab7+ late endosomal compartments. Expression of either tSNARE1b or tSNARE1c, which differ only in their inclusion or exclusion of a Myb-like domain, delayed the trafficking of known endosomal cargo, Neep21, into late endosomal and lysosomal compartments. These data suggest that tSNARE1 regulates endosomal trafficking in cortical neurons, likely through negatively regulating endocytic trafficking or maturation of early endosomes to late endosomes.