Submission
| Title: |
Phosphoproteomic Changes as an Early-Stage Predictive Indicator of Cortical Synaptic Dysfunction in Synucleinopathies |
| Co-Authors: |
Scott, Alicia, MCMP, Purdue University; Sayan Dutta MCMP Purdue University; Jennifer A. Hensel MCMP Purdue University; Rodrigo M. Ferreira University Dept. of Comparative Pathobiology Purdue; Jackeline Franco Dept. of Comparative Pathobiology Purdue University; Uma K. Aryal Dept. of Comparative Pathobiology Purdue University; Christina R. Ferreira Dept. of Comparative Pathobiology Purdue University, Laura A. Volpicelli-Daley Dept. of Neurology University of Alabama; Jean-Christophe Rochet MCMP Purdue University |
Abstract
Background/Significance/Rationale: Cortical dysfunction plays a critical role in non-motor symptoms associated with PD and other synucleinopathies. Recent studies have reported functional changes in cortical circuitry in pre-clinical models of PD, but with limited mechanistic insight. Therefore, in search of causative or predictive factors, we hypothesized that aSyn aggregation leads to alterations of the cellular proteome and lipidome.
Methods: To address this hypothesis, we utilized an in vivo model of aSyn aggregation involving the injection of aSyn preformed fibrils (PFFs) in rat striatum to study the downstream effects of aggregation. We further analyzed the global proteomic, lipidomic, and phosphoproteomic profiles of the cortical homogenates of the PFF injected vs monomer injected rats.
Results/Findings: In this model, we showed that PFF injection leads to the presence of aSyn aggregates that stain positive for the phosphorylated form of serine residue 129 (pSer129) in the sensorimotor cortex, SNpc, and other anatomically connected brain regions. Proteomic analysis of brain homogenates indicate that intrastriatally injected PFFs do not induce significant changes in the global proteome of the sensorimotor cortex compared to injected aSyn monomer 3 months post-injection. Similarly, no changes were observed in 13 lipid classes. However, analysis of the phosphoproteome of the sensorimotor cortex revealed significant differences between the PFF and monomer groups 3 months post-injection. Gene ontology analysis of the phosphoproteomic changes suggested that aSyn PFF administration led to perturbations in synaptic transmission. Moreover, we identified phosphosites that were previously not reported and distinct from sites reported for acute synaptic excitation.
Conclusions/Discussion: The phosphoproteomic changes suggest a possible mechanism of synaptic dysfunction in the sensorimotor cortex of PFF-injected rats.
Translational/Human Health Impact: Collectively, these findings deepen our understanding of the molecular underpinnings of synucleinopathy disorders, particularly the prodromal phase, laying the groundwork for developing well-tailored intervention strategies in the brains of patients.
