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PHL 437/Pharmacogenomics Fourth Lecture (Parkinson’s disease) By Abdelkader Ashour, Ph.D. Phone: 4677212

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Presentation on theme: "PHL 437/Pharmacogenomics Fourth Lecture (Parkinson’s disease) By Abdelkader Ashour, Ph.D. Phone: 4677212"— Presentation transcript:

1 PHL 437/Pharmacogenomics Fourth Lecture (Parkinson’s disease) By Abdelkader Ashour, Ph.D. Phone: 4677212Email:

2 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

3 Parkinson’s disease, Dopamine synthesis

4  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

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

6  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

7   -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.

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