Parkinson's disease (PD) type 1 (PARK 1) is a chronic neurological condition named after Dr. James Parkinson in1817, . PARK 1 affects approximately 1% of the population over age 50 (OMIM). Described as a slowly progressive disease, the affects are evident in small areas of the mid brain known as the substantia nigra, . Degeneration of these cells causes a reduction in dopamine, . The decrease in dopamine levels can produce the classic signs of Parkinson's disease such as resting tremors, bradykinesia, rigidity, and postural dysfunction, The National Parkinson Foundation (2001).

Studies of Parkinson's disease type1 phenotype suggests that alpha synuclein may provide a link to the cause of Parkinson’s disease and other neurodegenerative diseases.  Alpha-synuclein (SNCA or NACP) is located predominantly in the presynaptic nerve terminals in the brain and is found in low concentrations in all tissues except in the liver (SWISS-PROT).

Campion et al. (1995) mapped the NACP/synuclein gene to chromosome four. The alpha synuclein gene is located in region three of chromosome number four between 83,362K and 85,151K bp (NCBI). Through PCR-based analysis of human and rodent cells, the NACP gene was mapped to a cytogenetic band 4q21 .3-q22 by fluorescence in situ hybridization (FISH) Chen et al. (1995). Parkinson’s disease is viewed as an autosomal dominant inherited disease (OMIM). In documented family cases of PARK 1, penetrance of the gene was estimated to be 85% among family members with Parkinson disease (OMIM).  Parkinson’s disease, in general, is passed down from generation to generation, with an estimated fifty percent risk to an offspring of an affected parent.

The human alpha-synuclein gene belongs to a family synuclein genes (SPRINT). Each synuclein gene is characterized by three different proteins alpha, beta, and gamma (SPRINT). The overall structure of the synucleins is closely related by the amino acid sequences (SPRINT). Hydropathy analysis reveals a central hydrophobic domain of approximately thirty amino acids, with highly hydrophilic stretches of N-flanking regions containing repeated motifs EKTKEGV (SPRINT). The C domain contains glutamic acid and proline (SPRINT). Studies have shown that pathogenic mechanisms related to A53T mutations cause build up of precipitable SNCA aggregates and ubiquitin-immunoreactive inclusions in neurons within the neocortex, hippocampus, and substantia nigra (OMIM). Associated with a nine amino acid segment, the G-to-A transition in nucleotide 209 of the SNCA gene result in a ala53-to-thr (A53T) substitution Polymeropoulos et al. (1997) .This type of mutation commonly results in the loss of dopamingergic terminals in the basal ganglia, motor impairment, and essentially early onset of Parkinson's disease (OMIM).

The alpha-synuclein gene has 1549 base pairs within the mRNA sequence of figure 1 (SWISS-PROT). There are 471 adenines, 488 thymines, 248 cytosines, and 342 guanines within the mRNA complete sequence (SWISS-PROT). Six exons were found within this mRNA sequence of figure one and were distinguished by analayzing the intron and exon sequences found in figure 6C, figure 7, figure 8, and figure 9. The different highlighted sections of figure one indicate exon regions. The first exon is highlighted in gray, the second exon is highlighted in aqua blue, the third exon is highlighted in yellow, the fourth exon is highlighted in green, the fith exon is highlighted in purple, and the sixth exon is highlighted in red.

Alternative processing is indicated in the SNCA gene by the different types of exons found in the production of each of the various types of proteins. AAA16117 ( figure 2), AAA98493 ( figure 3), AAA98487 ( figure 4) , BAA06625 ( figure 5), and AAC02114 ( figure 6) are translated in each figure and the amino acid sequence is given for each protein sequence. The number of amino acid base pairs are given in each figure and the type of exons are highlighted in each sequence. The protiein identified as AAC02114 has two isoforms. Isoform A has 1683 base pair sequences and transcription starts at site 2701. The sequence of isoform A is in ( figure 6A). Isoform B has 1902 base pair sequences and transcription starts at site 2701. The sequence of isoform B is in ( figure 6B).

In residues 20 through 63 contains 4 X 11 AA tandem repeats of [EGS]-K-T-K-[EQ]-[GQ]-V-X(4) in figure 10 (SWISS-PROT). The three letter code is translated in figure 10A.  Repeat regions 20 through 30 are found in figure 11 and the translated three letter code is in figure 11A. Tandem repeat regions 31 through 41 are found in figure 12 and the translated three letter code is in figure 12A. Tandem repeats were also indicated in regions 42 through 56 in figure 13 and in regions 57 through 67 in figure 14. The three letter code of 42 through 56 is in figure 13A and the three letter code of 57 through 67 is in figure 14A.

Varient splicing information is found between 41 and 54 of figure 15 and between residues103 and 130 of figure 16. The three letter coding sequences of these figures are found in figures 15A and figure 16A.  Single variants are found at 30 loci of figure 17 and 53 of figure 18 within the single letter coding sequences. The three letter coding sequence of figure 17 is in figure 17A, and the three letter coding sequence of figure 18 is in figure 18A.

< Alpha-synuclein mutations are known to exist in several families with autosomal dominant Parkinson's disease. A single peptide of the alpha synuclein protein has been characterized as a major component of amyloid plaque formations in the brain (SWISS-PROT). The mechanism that causes the presynaptic protein to create neurodegenerative disorders, such as Parkinson's disease, is still unclear (SWISS-PROT).

The recent completion of the human genome has opened many doors to understanding the functionality of our genes and the cause of many genetic disorders.Parkinson's disease and many other genetic disorders are under investigation in hopes of curing or preventing its onset. By understanding the genetic conditions that cause Parkinson's disease, scientists may one day be able to utilize gene therapy as a preventative measure in the fight against this genetic disorder.

Work Cited

Chen, X.; Rohan de Silva, H. A.; Pettenati, M. J.; Rao, P. N.; St. George-Hyslop, P.; Roses, A. D.; Xia, Y.; Horsburgh, K.; Ueda, K.; Saitoh, T. :

The human NACP/alpha-synuclein gene: chromosome assignment to 4q21.3-q22 and TaqI RFLP analysis. Genomics 26: 425-427, 1995.
PubMed ID : 7601479

National Center for Biotechnology Information (NCBI), Homo sapiens Map View,

Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276: 2045-2047, 1997.
PubMed ID : 9197268

SPRINT, PRO1212,