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

PHL 437/Pharmacogenomics

Fourth Lecture (Parkinson’s disease)

By

Abdelkader Ashour, Ph.D. Phone: 4677212 Email: [email protected]

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 Ca2+ 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 Ca2+ 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

Gq

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.