Parkinson's Disease Research Paper

Parkinson’s disease (PD) is one of the major neurodegenerative disorders characterized by a substantial loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), resulting in irreversible motor symptoms consisting mainly of tremors, bradykinesia and rigidity. Although the pathology and clinical symptoms are well defined in PD, the cellular and molecular mechanisms underlying the selective degeneration of dopaminergic neurons remain unknown. Lack of such fundamental knowledge severely hinders the development of neuroprotective strategies to circumvent the chronic progression of this debilitating neurodegenerative disorder.

Recent investigations in animal models and in post-mortem human brain tissues have demonstrated that

Our recent studies have shown that inflammatory cytokine TNF induces reactive oxygen species via NADPH oxidase that causes oxidation of phospholipids to phospholipid hydroperoxide and Azelaoyl phosphotidadyl choline (Scheme 1) and increases Platelet-activating Factor (PAF) in non-neuronal cells, and I expect brain and nervous tissues are also very susceptible to oxidation due to their high level of polyunsaturated fatty acids and intense consumption of oxygen. Furthermore, TNFα receptor 1 is highly expressed on dopaminergic neurons, and their expression increases in PD (). More significantly, Oxidatively truncated phospholipids are internalized, migrate to mitochondria, and then disrupt mitochondrial function, in a way aided by Bid, to initiate intrinsic apoptosis (23, 24). PAF and oxidatively truncated phospholipids, a proinflammatory lipid mediators bind to the G-protein coupled transmembrane receptor, the

Specific Aim I: To determine if oxidation of phospholipids in dopaminergic neurons in SNpc induces neurodegeneration in animal models (MPTP and 6-OHDA) as well as in human post-mortem PD tissues. Oxidation of phospholipids and PAF will be determined in SNpc in animal models of PD by using LC/MS/MS (). The enzyme PAF acetylhydrolases 2 (PAFAH2) uniquely distinguish oxidatively modified phospholipids from biosynthetic, unmodified phospholipids because they very strongly select substrates with short sn-2 residues (18, 25). Hydrolysis of oxidatively damaged phospholipids may be the original role of this family of phospholipases A2 (26), and overexpression of the family member PAFAH2 in mammalian cells reduces toxicity to exogenous ROS (27). PAFAH2 will be knocked-in in neuronal cells using CRISPR/Cas9. Recently, the RNA-guided endonuclease Cas9 from microbial type II CRISPR systems has been harnessed to facilitate genetic manipulation in a variety of cell type and organisms. CRISPR/Cas9 can target genes in adult neuronal cells [84–86], it can be applied to the brains of adult animals via stereotaxic injection of viral expression vectors. Such application may limit mosaic and off-target effects, and