Genetic Contributors to Non-Motor Symptoms of Sporadic Parkinson's disease
Open Access
- Author:
- Tekin, Izel
- Graduate Program:
- Pharmacology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- November 05, 2015
- Committee Members:
- Kent Eugene Vrana, Dissertation Advisor/Co-Advisor
Kent Eugene Vrana, Committee Chair/Co-Chair
Richard Bernard Mailman, Committee Member
Xuemei Huang, Committee Member
Willard M Freeman, Committee Member
Carla Jean Gallagher, Committee Member - Keywords:
- Parkinson's disease
SNP
Catecholamine
Genetics
Next Generation Sequencing - Abstract:
- Parkinson’s disease (PD) arises from the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. In addition to the dopaminergic structures, PD pathology is also observed in areas of other neurotransmitter systems. One of the most significant of these systems, and the main topic of this dissertation, is the noradrenergic system. Dopamine and norepinephrine are synthesized by enzymes that are found in the catecholamine biosynthesis pathway. Specifically, tyrosine hydroxylase (TH) catalyzes the conversion of the amino acid tyrosine to levodopa (L-DOPA), which is the rate-limiting step in catecholamine biosynthesis. L-DOPA is then converted to dopamine (DA), which is then converted to norepinephrine (NE) by dopamine beta hydroxylase (DBH). It is interesting that both of these neurotransmitters are important in PD and they share common steps in their synthetic pathways. A common polymorphism in TH has been shown to be associated with more severe freezing of gait (FOG) in PD patients. FOG is a symptom that usually occurs in the later stages of the disease. In subjects that are homozygous for the V81M single nucleotide polymorphism (SNP), the FOG is more severe. Heterozygous subjects are unaffected, which is in agreement with observations from TH knockout animals. When transgenic mice contain one intact copy of TH, they are able to synthesize catecholamine levels equal to those of the wild type animals. The conversion of valine to methionine causes an increase in the Michaelis-Menten constant of TH for its substrate tyrosine, when assayed in vitro. This may result in a decrease in catecholamine synthesis as the rate-limiting enzyme will be less efficient. This finding supports the previously reported role of NE in the development of FOG. PD patients with FOG have lowered NE and in certain cases, FOG can be resolved by administration of NE mimetics. In addition to its role in FOG, NE has also been implicated in PD pathology. Noradrenergic neurons in the locus coeruleus (LC) also show increased neurodegeneration and accumulation of alpha-synuclein-containing Lewy Bodies (LB), which are present in dopaminergic neurons. Animal studies have suggested that NE can be neuroprotective against dopaminergic neurodegeneration. In line with these data, a rare SNP (R549C) in the enzyme DBH was observed significantly more in PD subjects compared to controls. The expression of DBH in sera obtained from heterozygous subjects was less than WT sera. There is also a possible effect of R549C on the oligomerization of the enzyme; however, this requires further investigation. Heterozygous R549C sera have increased conversion of tyramine to octopamine as measured by spectrophotometry. This may be interpreted as increased DBH activity in heterozygous subject sera; however, this assay is not DBH-specific. These results can be interpreted in several ways: the decreased expression of DBH results in compensatory changes increasing enzyme activity or this observation is merely an artifact or there is significant increase in DBH activity in CNS of patients with this SNP. The clinical observation in which DBH R549C is associated with PD may be due to a decrease in NE neuroprotection or reduced DA levels due to increased DBH activity. In summary, genetic changes in the catecholaminergic pathway and the resulting alterations in the regulation of this system may underlie PD pathology and characteristics. Elucidation of genetic changes in PD endophenotypes will illuminate different pathological contributors to the disease. In a complex disorder such as PD, dissecting the molecular pathways and their roles is key to understanding disease pathology, which will lead to more successful disease management and generation of improved therapies.