Parkinson's disease (PD) is one of the most prevalent neurodegenerative movement disorders, and abnormal a-synuclein (a-syn) aggregation and mitochondn.al dysfunction play central roles in the pathogenesis. The ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway, as the major degradation pathways cellular protein quality control systems, play significant roles in a variety Of neurodegenerative diseases characterized primarily by abnormal protein aggregation, including PD, Alzheimer's disease and Huntington's disease. In addition, autophagy degrades not only abnormal proteins but also protein aggregates and damaged subcellular organelles to maintain cellular homeostasis. Studies have shown that upregulation of UPS and autophagy activity can alleviate the neuropathology of neurodegenerative diseases, which is a promising therapeutic strategy. In the study of chapter two, through a high throughput screening of u-syn reducing compounds, lycorine was identified as a natural UPS enhancer. Functional analysis shows that lycorine significantly promoted clearance of over-expressed wild-type (W T) and mutant a-syn in neuronal cell lines, and in primary cultured neurons isolated from A53T transgenic mice. More importantly, 15 days intraperitoneal administration of lycorine effectively promoted the degradation of a-syn in the brain of A53T transgenic mice in an autophagy-independent and UPS-dependent manner, Lycorine accelerated UPS-mediated degradation not by affecting protein ubiquitination but by enhancing proteasome activity. Mechanistically, lycorine increased the level of CAMP, thereby activating the cAMP-dependent protein kinase (PKA) to promote the proteasome activity both in vitro and in vivo. These results indicate that lycorine is a novel a-syn lowering compound though PKA-mediated UPS activation, implying the development potential of lycorine for the treatment of neurodegenerative diseases associated with UPS impairment and proteins aggregations. Corynoxine B (Cory B), one of the major alkaloids found in Uncaria rhynchophylla (Miq.) Jacks, Rubiaceae, has been reported to activate phosphatidylinositol-3 kinase Ill (P13KC3) and induce autophagy in a mTOR independent manner, promoting the elimination of neurotoxic proteins in multiple cellular models of PD. In the study of chapter three, we found that Cory B promoted the activity of Beclin1/VPS34 complex and increased autophagy by directly binding HMGB1/2. Similar to HMGBI, HMGB2 can bind to Beclinl to enhance autophagy. HMGB2 knockdown or Hmgb2 knockout cells showed lower autophagy levels and P13KC3 activity compared with WT N2a cells. Treatment with Cory B restored autophagy, promoted a-syn clearance and improved behavioral abnormalities in a mouse model of PD induced by overexpressing mutant a-syn (A53T). Taken together, this study supports that Cory B regulates P13KC3 activity/autophagy by modulating HMGB1/2 and enhancement of this process is a neuroprotective strategy against PD development.