An insight into alpha synuclein’s biological function and  its pathogenesis in neurodegenerative disease 
Gilbert Gallardo
Abstract
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.  CSPa 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 CSPa deficient mice have impaired SNARE complexes that are partially reverted by transgenic a-synuclein.  This study illustrates a protective function of alpha-synuclein in preventing neurodegeneration.