Schizophrenia is a polygenic neuropsychiatric disorder characterized by delusions and hallucinations, which lacks effective, targeted therapies. Recently, the largest genome wide association study on schizophrenia to date identified 108 loci as associated with the occurrence of schizophrenia. The fifth most significant hit mapped to a locus containing the gene TSNARE1, which encodes the protein t-SNARE domain containing 1 (tSNARE1). tSNARE1 has two isoforms, which contain a N-terminal c-Myb DNA binding domain and a C-terminal Qa SNARE domain. Rare variant mutations that were identified from patients with either schizophrenia or autism spectrum disorder suggest the SNARE domain is critical for its function. Unlike canonical Qa SNARE proteins, the primary neuronal isoform, tSNARE1b, lacks a transmembrane domain as well as any other predicted site for membrane attachment, which is necessary for membrane fusion. Therefore, my central hypothesis is that tSNARE1b acts as an inhibitory SNARE (i- SNARE) of certain membrane trafficking events. To test this hypothesis, I will first determine to which compartments tSNARE1b localizes within the endosomal and autophagy networks by performing high resolution, live-cell confocal microscopy of tSNARE1b-GFP and spectrally distinct markers of the compartments. I will then determine the effect of tSNARE1b on the intersection of membrane trafficking between late endosomes, lysosomes, and autophagosomes with three-color, live-cell imaging. Understanding the cellular and physiological role of tSNARE1b is necessary towards understanding how its dysfunction may contribute to schizophrenia and other neuropsychiatric disorders. Therefore, we will repeat the above experiments with the rare variants of tSNARE1b to determine how these mutations disrupt membrane trafficking at the intersections of endocytosis and autophagy. Finally, we will collaborate with core facilities to generate and characterize a knock-in mouse model overexpressing TSNARE1 or a rare variant to assess its effects on behavior and neuronal connectivity and morphology.
tSNARE1 has recently been implicated as a risk factor for schizophrenia and other neuropsychiatric disorders, yet nothing is known about its cellular and physiological function. Determining how this unstudied protein regulates membrane trafficking and how its dysfunction leads to neuronal and behavioral abnormalities is critical towards understanding how it contributes to neuropsychiatric disorders.
