Cell-specific phosphoproteomic profiling in a mouse model of autism linked to a dysregulated kinase
- Awarded: 2023
- Award Type: Pilot
- Award #: AR-PI-00002388
Many kinases have been linked to monogenic subtypes of autism spectrum disorder (ASD), but their role in the mechanisms underlying disease etiology is not well understood. ASDs, like other neurodevelopmental conditions, are poised to be associated with deficiencies in specific cell types, neurons or glia in the brain, as suggested by single cell RNA sequencing (RNA-Seq)1–3. However, the proteome, let alone the phosphoproteome, have not been well studied, and cell-type-specific studies are in their infancy.
Heike Rebholz and her colleagues are primarily interested in Okur-Chung neurodevelopmental syndrome (OCNDS), a condition characterized by developmental delays, intellectual disability and ASD. It is linked to variants in the CSNK2A1 gene, which encode casein kinase II (a serine/threonine protein kinase). The team has previously detected changes in the phosphoproteome of three patient-derived fibroblast lines4.
In this project, the researchers plan to extend on these studies by using state-of-the-art in vivo cell-type-specific proteome labeling, based on the integration of a non-canonical amino acid into the proteome, followed by quantitative mass spectrometry to uncover dysregulated signaling pathways in a mouse model of OCNDS, CK2aK198R5. In a proof-of concept study, they will use this technology to characterize the proteome and phosphoproteome of the two primary striatal neuron types (direct and indirect medium spiny neurons) that are known to play a role in ASD-relevant behaviors and to harbor differently regulated signaling pathways and project to different output structures. They expect to find converging and differential proteomic signatures that will help to uncover changes caused by the disease-causing mutation in the mouse model. A similar approach can be extended to other kinase-driven ASD subtypes to delineate cross-subtype phosphoproteomic signatures associated with pathophysiology.