Role of Alpha‐Synuclein in Parkinson's Disease

Abstract

While Parkinson's Disease is a multifactorial disease, influenced by both genetics and the environment, alpha-synuclein was the first genetic factor to be linked to the disease. It has henceforth become a target in therapeutic research. A-synuclein is a 140 amino acid neuronal protein that primarily regulates synaptic activity. It is considered to be intrinsically disordered as it does not have a defined structure in aqueous solutions. However, the protein forms α-helical structures when it binds to negatively charged lipids, such as phospholipids in cell membranes. Α-synuclein is a member of the synculein protein family, a group of three neuronal proteins with a highly conserved alpha-helical lipid binding domain. Synucleins have been associated with a number of neurodegenerative disorders, including Parkinson's Disease (PD) and Alzheimer's Disease (AD), as well as some cancers. A-synuclein is unique in the synuclein family for its non-amyloid component (NAC) region, which has been linked to the formation of Lewy bodies. The wild type form of α-synuclein is coded from the SNCA gene. This form has several functions, but it primarily functions as a presynaptic protein that controls neurotransmitter release by acting as a chaperone in the folding of Soluble NSF Attachment Protein Receptors (SNAREs). SNAREs mediate vesicle fusion with membranes, while α-synuclein increases local Ca2+ release from microdomains to trigger ATP-induced exocytosis. Certain mutations in SNCA cause α-synuclein to polymerize into protofibrils that eventually coalesce into fibrils, a process called α-synuclein aggregation. Aggregation of α-synuclein leads to the creation of Lewy bodies, toxic clumps in the brains of patients with PD. PD is a progressive neurodegenerative disorder that affects movement. Common symptoms include bradykinesia, muscular rigidity, and tremor. Some studies have shown that deleting the NAC region prevented aggregation of α-synuclein. Other α-synuclein therapies have used receptor blocking strategies to inhibit the spread of the protein to other parts of the brain. There are also a variety of therapies that focus on preventing aggregation by decreasing the amount of α-synuclein in the brain. While such therapies have shown positive results in fruit flies, mice, and rats, human trials have not been conducted. Medications to control symptoms are the main treatment for PD; these medications typically work by increasing or acting as a substitute for dopamine, as PD patients have low dopamine concentrations. In severe cases, surgeries like deep brain stimulations have helped to lessen tremors. Patients are encouraged to make lifestyle changes, such as uptaking aerobic exercise or physical therapy, which can improve symptoms. Further research on the relationship between α-synuclein and Parkinson's Disease is required before human trials can begin. Nonetheless, the results of therapeutic studies have been promising.