Title : Combinatorial model of traumatic brain injury and parkinson’s disease: Investigating alpha-synuclein acetylation and its role in proteasome dysfunction, apoptosis, and neuroinflammation
Abstract:
Introduction: Traumatic brain injury (TBI) and Parkinson’s disease (PD) are major neurological disorders that significantly impact quality of life. Recent research suggests a potential link between them, particularly through the effects of repetitive mild traumatic brain injury (rmTBI). Such injuries may trigger or exacerbate neurodegenerative processes, leading to the onset and progression of PD. A key player in this relationship is alpha-synuclein (α-syn), a protein associated with PD pathology. This study aims to investigate how the acetylation of α-syn influences neurodegenerative pathways following rmTBI, thereby enhancing our understanding of the mechanisms linking TBI and PD.
Objective: The objective of this research is to develop a combinatorial rodent model to investigate how rmTBI influences the progression of PD, particularly examining the implications of α-syn acetylation in neuroinflammation and proteasome dysfunction.
Methodology: Swiss albino mice were subjected to 30 days of repetitive mild traumatic brain injury (rmTBI) to simulate the effects of brain trauma. Following this period, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was administered to induce Parkinson’s disease-like symptoms. The mice were categorized into three distinct groups: Sham (no intervention), PD-only (only MPTP treatment), and TBI + PD (rmTBI followed by MPTP). After the experimental phase, a variety of molecular and biochemical techniques were utilized to investigate acetylated proteins in brain lysates. These techniques included Western blotting, immunohistochemistry (IHC), high-resolution mass spectrometry (HRMS), RNA sequencing, and RT-PCR to comprehensively analyze the molecular changes.
Results: Our findings indicate a significant increase in α-syn acetylation levels in the TBI + PD group compared to both the PD-only and Sham groups. Additionally, the TBI + PD group exhibited notable proteasome dysfunction, elevated markers of apoptosis and necrosis, and heightened neuroinflammatory responses. RNA sequencing results revealed the upregulation of genes associated with neuroinflammation and stress responses, correlating with the observed changes in acetylation.
Conclusion: This research supports the hypothesis that α-syn acetylation drives neurodegenerative processes, particularly when TBI precedes PD. By elucidating the molecular mechanisms linking acetylation to neuroinflammation and proteasome impairment, this study identifies potential therapeutic targets for PD, particularly in patients with a history of brain trauma. Our findings enhance the understanding of the interplay between TBI and PD progression, contributing valuable insights to the field of neurodegenerative research.
