An Insight into Alpha-Synulcien's Biological Function and Its Pathogenesis in Neurodegenerative Disease

The discovery of two missense mutations (A53T and A30P) in alpha -synuclein that are genetically linked to Parkinson's disease, together with alpha -synuclein being the major component in Lewy bodies, has generated extensive interest in alpha -synuclein as a key component in neurodegenerative diseases. In recent years modeling this disease in transgenic mice and flies has lead to new understandings of alpha -synuclein function and pathogenesis in neurodegeneration. In the current study we analyzed transgenic mice overexpressing human alpha -synuclein and human alpha -synuclein mutations (A53T&A30P) to; First establish these transgenic mice as a model for degenerative diseases; second to identify potential contributing factors in neurodegeneration; third to decipher a potential function of alpha -synuclein. We first established that transgenic mice expressing human variants of alpha -synuclein developed an age dependant motor dysfunction with symptom logy characteristic of Parkinson's disease. Immunohistological studies revealed the presence of alpha -synuclein inclusions and a loss of motor neurons. Biochemical analysis identified a 4-5 fold increase in ubiquitin with altered expression of proteasomal subunits, characteristic of proteasomal impairment. In addition, we identified a significant increase in amyloid beta -peptides. Protein quantification of apolipoprotein E (ApoE) a protein that has been associated with the development of Alzheimer's disease, demonstrated a 5-15 fold increase in symptomatic transgenic mice. Ablation of ApoE in alpha -synuclein transgenic mice by genetic crosses revealed a delayed onset for motor dysfunction and an overall increase in survival. ApoE deficient transgenic mice displayed a decrease in ubiquitin and amyloid beta -peptides. This study illustrates ApoE, ubiquitin and Abeta - peptides contribute to the onset and progression of the neurodegeneration in transgenic alpha -synuclein mice. Genetic crosses of transgenic alpha -synuclein with a csystine string protein-alpha (CSPalpha ) knockout mouse revealed a potential function for alpha -synuclein. CSPalpha deficient mice develop an early age neurodegenerative disease that is lethal at 3-4 months. Transgenic expression of human alpha -synuclein prevented the deleterious effects of CSPalpha deficiency. Immunofluorescence studies illustrated alpha -synuclein function in a cell autonomous manner. Biochemical analysis demonstrated CSPalpha deficient mice have impaired SNARE complexes that are partially reverted by transgenic alpha -synuclein. This study illustrates a protective function of alpha -synuclein in preventing neurodegeneration.