Zhao, Yibo; (2024) LRRK2 Protein Interactome in Health and Parkinson’s Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: Mutations in LRRK2 are the most common genetic cause of familial Parkinson’s disease (PD). However, the physiological/pathological roles of LRRK2 are still unclear. This project aims at collecting the vast data of LRRK2 research and integrating them in a homogeneous, computational model to describe LRRK2’s activity in physiological and pathological pathways. Method: The protein interactome of LRRK2 was built in consecutive steps: 1) peer-reviewed protein-protein interactions (PPIs) were derived to define the general LRRK2 interactome (LRRK2int); 2) interactions among LRRK2 interactors were derived to construct the LRRK2-centred protein-protein interactions network (LRRK2net); 3) topological analysis was performed on the LRRK2net to identify clusters of LRRK2 interactors with high-density PPIs; 4) each topological cluster was functionally annotated; 5) the LRRK2net were then merged with transcriptomic data of healthy human tissues to define the tissue specificity LRRK2 interactors; 6) the LRRK2net was merged with transcriptomic and genomic data of patients with sporadic PD, LRRK2 genetic PD and healthy controls to investigate the molecular mechanisms of the 2 types of PD. Results: A total of 418 proteins were included in the LRRK2int, involving a range of different protein families. PPIs among these interactors formed a scale-free network, in which 7 topological clusters with biological significance were identified, associated with ribosomal biosynthesis, cytoskeleton dynamics, synaptic transport, mitophagy and protein metabolism. LRRK2 interactors presented distinct expression signatures and functional patterns in the brain and the periphery. Of note, a striatal unit of putamen, caudate and nucleus accumbens was identified where LRRK2 interactors presented the highest co-expression with LRRK2 and similar expression profiles. At last, PD-associated expression analysis identified 100 LRRK2 interactors with significant differential expression in PD cases vs. control. Conclusion: This study defined a comprehensive protein interactome of LRRK2 with high tissue specificity and substantial association with sporadic PD and LRRK2-related PD.

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