Investigation of the Effects of BRCC3 Gene Knockout on Autophagy and Endoplasmic Reticulum Stress Pathways in a Rotenone-Induced Parkinson's Disease Model
Project no. 23270 · Status: Kapanmış · 2021
Summary
<p>Parkinson's Disease (PD) is a common neurodegenerative disorder affecting approximately 1-3% of the global population aged sixty and above. Studies indicates that disruptions in the ubiquitin-proteasome system (UPS) and autophagy mechanisms, responsible for the degradation of misfolded or malfunctioning proteins within cells, triggers PD-associated biological processes such as α-synuclein aggregation, neuroinflammation, and endoplasmic reticulum stress (ERS).</p><p>The main purpose of this thesis study is to investigate the effects of BRCC3 (BRCA1-/BRCA2-containing complex 3) gene knockout, which is known to be involved in the regulation of UPS and inflammasome activation processes, on autophagy and ER stress in <em>in vitro</em> and in vivo PH models created with rotenone. In pursuit of this purpose, the effects of BRCC3 gene knockout performed with niosome-siRNA complex in the <em>in vitro</em> PH model created in primary dopaminergic neuron lines obtained from rat embryos were investigated by simultaneous polymerase chain reaction (RT-qPCR) analyses, and the findings obtained from these analyzes showed that BRCC3 gene knockout affects autophagy and It has been shown that genes involved in ERS have a protective effect on dopaminergic neurons by regulating their mRNA expression.</p><p>Within the scope of the thesis study, the effects of BRCC3 gene knockout performed with niosome-siRNA complex on the in vivo PH model created in rats by rotenone injection were evaluated with behavioral experiments, histochemistry, immunohistochemistry, biochemistry and RT-qPCR analyses. The findings from these analyses, similar to those in the <em>in vitro</em> studies, demonstrate that BRCC3 gene knockout exerts a protective effect by regulating the mRNA expressions of genes involved in autophagy and ERS and reactivating the antioxidant system, thereby alleviating histopathological changes and motor function defects resulting from rotenone exposure.</p><p>In conclusion, the findings we obtained within the scope of our thesis study, in which the effect of BRCC3 gene knockout on autophagy and ERS in <em>in vitro </em>and <em>in vivo</em> PH models were investigated, show that BRCC3 may be a potential therapeutic target in the treatment of PD.</p><p><strong>Keywords</strong>; BRCC3; Endoplasmic Reticulum Stress; Gene Knockout; Autophagy; Parkinson's Disease; siRNA</p>