On 28 September Ye Hong from Laura Elo’s and Eleanor Coffey’s groups defended her thesis in Bioinformatics titled “Evaluation of the relevance and impact of kinase dysfunction in neurological disorders through proteomics and phosphoproteomics bioinformatics analysis”. Ye’s opponent was Prof. Jacques Colinge from University of Montpellier, France.

Congratulations Ye!

Abstract:

This dissertation explores the world of protein phosphorylation, a critical post-translational modification that plays a key role in cellular functions. The focus is on the neurological disorders of schizophrenia and Parkinsons disease, specifically investigating the phosphoproteome and protein abundance.

Study I introduces PhosPiR, an automated analysis pipeline in R, aimed at streamlining the proteomics and phosphoproteomics data processing. This tool can perform a multi-level functional analysis of MS data and supports 18 different organisms. It offers a comprehensive approach to MS data analysis, including preprocessing, normalization, enrichment analysis, network analysis, and more.

Study II investigates the LRRK2-G2019S mutations function in the brain, specifically its localization to the small 40S ribosomal subunit and suppression of RNA translation. The findings were validated using different models, including Parkinsons disease patient cells.

Study III uses bio-orthogonal non-canonical amino acid tagging to identify nascent proteins affected by repressed translation. The analysis reveals significant changes in specific biological processes, which were further validated through targeted proteomics and immunoblotting.

Study IV focuses on the role of JNK1 in schizophrenia. Using wild type and Jnk1-/- mice, LC-MS/MS analysis identifies 126 schizophrenia-associated proteins that overlap with significantly differentially phosphorylated proteins in the Jnk1-/- mice brain. The study highlights the NMDAR trafficking pathway and shows a decrease in surface expression of NMDAR subunits in Jnk1-/- neurons. Behavioral tests further link the Jnk1-/- molecular and behavioral phenotype with schizophrenia and neuropsychiatric disease.

The insights into the LRRK2-G2019S mutations role in Parkinsons and the phosphorylation profiles connection to schizophrenia pave the way for potential new therapeutic interventions.

Download full dissertation.