PHL 437/Pharmacogenomics Fourth Lecture (Parkinson’s disease) By Abdelkader Ashour, Ph.D. Phone:

Parkinson’s disease, Introduction  Parkinson’s disease (PD) is a common neurodegenerative disease whose clinical picture includes four cardinal features:  bradykinesia (slowness of movement)  muscular rigidity  resting tremor (which usually abates during voluntary movement)  impairment of postural balance leading to disturbances of gait and falling  Progressive loss of dopamine-containing neurons is a feature of normal aging; however, most people do not lose the 70% to 80% of dopaminergic neurons required to cause symptomatic PD. Without treatment, PD progresses over 5 to 10 years to a rigid, akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism  The pathological hallmark of PD is a loss of the pigmented, dopaminergic neurons of the substantia nigra pars compacta that provide dopaminergic innervation to the striatum, with the appearance of intracellular inclusions known as Lewy bodies

Parkinson’s disease, Dopamine synthesis

 All the dopamine receptors are heptahelical G protein-coupled receptors  Initially, two types of dopamine receptors were identified in the mammalian brain:  D1 receptors, which stimulate the synthesis of the intracellular second messenger cAMP  D2 receptors, which inhibit c AMP synthesis, suppress Ca 2+ currents and activate receptor-operated K +  At present, five distinct dopamine receptors are known, which can be divided into two groups on the basis of their pharmacological and structural properties  The D1 and D5 receptors are members of the class defined pharmacologically as D1; they stimulate the formation of cyclic AMP and phosphatidyl inositol hydrolysis  The D2, D3, and D4 receptors are of the D2 class. They decrease cyclic AMP formation and modulate K + and Ca 2+ currents Parkinson’s disease, Dopamine receptors

G-protein-Coupled Receptors, Targets  PIP2: phosphatidylinositol- 4,5-bisphosphate  IP3: inositol-1,4,5- trisphosphate  DAG: 1,2-diacylglycerol PIP2 GqGq

 Anti-PD drugs, such as levodopa and the direct-acting dopamine agonists, are effective in reducing the motor symptoms of PD  However, these drugs are also associated with the development of motor complications, such as levodopa-induced dyskinesia (LID), response fluctuations and side effects, such as hallucinations and excessive daytime sleepiness  Genetic variability in genes coding for drug-metabolizing enzymes, drug receptors and proteins involved in pathway signaling is an important factor determining interindividual variability in drug response  Positive associations were found between the occurrence of LID and polymorphisms in the dopamine receptor D2 gene and the dopamine transporter gene  Motor fluctuations have been associated with a D2 gene polymorphism  Associations were found between sleep attacks without warning signs and a polymorphism in the D4 gene, the D2 gene and the catechol-O-methyl transferase (COMT) gene  In clinical practice, a large interindividual variability in drug response has been noticed Up to 45% of levodopa users develop LID within 5 years, while others remain free of LID for many years Up to 25% of users of dopaminergic drugs develop hallucinations, whereas others do not Parkinson’s disease, Pharmacogenomics

  -Synuclein is a monomeric protein of 140 amino acids, normally soluble and unfolded, which preferentially locates within the synaptic endings of central nervous system neurons  Recent studies, though, established a primary role for  -synuclein in the formation of Lewy bodies, and its aggregation in insoluble amyloid fibrils seems to precede the accumulation of ubiquitin and neurofilaments  Mutant forms of  -synuclein, such as those linked to autosomal dominant forms of Parkinson’s disease, exhibit accelerated self-aggregation into fibrils, probably fostering Lewy body development Parkinson’s disease, Pharmacogenomics, contd.