Genetic Basis to Parkinson’s Disease
Angela Lee
BIOL 303
Parkinson’s Disease is a common neurological disorder. The disease is defined by dopaminergic neuron loss in the substantia nigra. The loss of these neurons results in the characteristic tremors, rigidity, and bradykinesia commonly associated with the disease. The disease is treatable but not curable and progresses to the point that it becomes fatal because of the eventual degradation of the brain stem. (Biological Psychology 2007)
In the last two decades advancements in genetic research have enabled researchers to pinpoint the genetic causes of Parkinson’s. The a-synuclein gene is implicated as the cause of autosomal parkinsonisms through its dosage. The most notable genetic causation was in the triplication of the SNCA gene. To determine whether a simple duplication or 3 copies of SNCA could be responsible for familial Parkinson’s forms, Ibanez et al. (2004) drew from a population of 119 index patients for the presence of the rare autosomal dominant form of Parkinson’s. The dosage of SNCA was determined through PCR amplification. The exons 3 and 4 were amplified along with exon 4 of the Parkin gene and a 236 bp sequence of the transthreytin gene. The Parkin gene and the transthreytin gene are both used as normalization controls. The genes were amplified through PCR, sequenced by AB13100 automated sequencer, and analyzed through Genescan 3.1.2 and Genetyper1.1.1 software. After 23 cycles of amplification the ratio of peak heights of exons 3 and 4 and the control genes were compared with the ratios of control subjects. Three copies of the SNCA gene were amplified from patients known to have duplications of the gene and compared to 2 copies from control patients without duplications. Out of these 119 index patients, 115 had normal peak height ratios, 2 patients had ratios implicating duplications and 2 patients were inconclusive. The two duplicated patients were analyzed further using microsatellite markers to determine the location of the duplications. Results of this analysis showed that the duplications differ in size, one duplicated the region from NACPREP1 to D4s2304 and the other duplicated the region from D4s2458 to D4s2304. Both of these regions encompass the entire SNCA gene. The two patients with duplications had symptoms indicative of idiopathic Parkinson’s. Though they had three copies of the SNCA gene, their Parkinson’s was indistinguishable from that of patients with two copies of the SNCA gene in contrast to the severity of Parkinson’s evident in patients with four copies of the SNCA gene due to a heterozygous triplication.
A family carrying the autosomal dominant form of Parkinson’s was chosen as the focus of a second study because of its profound pathology with an average onset of 34 years, presence of Lewy Bodies, a hallmark of Parkinson’s, and glial cell cytoplasmic cell inclusion (Singleton et al. 2001). Quantitative real time PCR amplification of SNCA provided evidence of triplication. The extent of the triplication was determined to be between 1.61 Mb and 2.04 Mb. After multiple tests of many varieties Singleton et al were finally able to determine that the SNCA gene triplication is responsible for the severe form of early onset Parkinson’s. The authors concluded that because of the predicted four copies of SNCA the quantitative properties, as opposed to the qualitative, of the triplication lead to Parkinson’s.
One of the most common treatments of Parkinson’s is synthetic dopamine known as the drug Levodopa (Biological Psychology 2007). This synthetic dopamine reacts well with patients at first but it inhibits natural dopamine production and becomes detrimental after continuous use. One new method for treating Parkinson’s is gene therapy. Kaplitt et al. (2007) attempted this treatment using a viral vector of this treatment to increase gamma- aminobutyric acid, or GABA production in the subthalamic nucleus. GABA is the major inhibitory neurotransmitter in the brain and increased production leads to suppression of the overly active subthalamic nucleus, alleviating the debilitating symptoms of advanced Parkinson’s disease. Essentially by reinstating GABA production, Parkinson’s could be effectively treated. Twelve patients selected for this study all with advanced Parkinson’s of a duration of at least 5 years were selected for this study. All of the patients received surgery, 4 received a low dose of gene therapy treatment, 4 received a medium dose, and 4 received a high dose. Positive improvements in motor function were noted three months after the high dosage therapy and this improvement lasted for the year in which this trial was conducted. These results showed that the gene therapy was a safe form of treating Parkinson’s.
Though evidence suggests a genetic component to Parkinson’s, it is still not clear what events cause its onset. There are many hypotheses ranging from the suggestion of caffeine intake to the more substantial belief that exposure to certain toxins combined with unhealthy lifestyles can lead to the disease ( Investigation into possible causes of Parkinson’s disease compare caffeine intake of family members with PD to the intake of family members without PD (Facheris et al 2008). The intake of coffee was determined through survey questions focusing on the time before the onset of the disease for affected family members, but no relationship to Parkinson’s was observed. In addition, the genes, ADORA2A and A2a, which both produce proteins active in caffeine metabolism were analyzed for SNPs that might be risk factors for Parkinson’s. However, no SNPs in either gene were tied to Parkinson’s. Thus, the study was not able to support the hypothesis that coffee protects against Parkinson’s.
Genetics has a key role in the manifestation and treatment of Parkinson’s disease. Further research can improve understanding behind what causes the disease to manifest. As Kaplitt et al. (2007) have shown, genetic research also can lead to improved methods of therapy and treatment of PD. As the investigation into the relationship betweens genetics and PD continues, possible methods of prevention undoubtedly will be uncovered as well.
Works Cited
Biological Psychology. 9th ed. Belmont, CA: New Leaf, 2007. 254-58.
Facheris, Maurizio F,Schneider NK, Lesnick TG, de Andrade M, Cunningham JM, Rocca WA, Maraganore DM. "Coffee Caffeine Related Genes, and Parkinson's Disease: A Case- Control Study." Movement disorders 23 (2008): 2033-040.
P . Ibáñez, A . Bonnet, B . Débarges, E . Lohmann, F . Tison, P . Polla , Y . Agid, A . Dürr, A . Brice. “Causal relation between α-synuclein locus duplication as a cause of familial Parkinson's disease.”The Lancet 364 (2004): 1169-171.