423Role of Pharmacogenetics in Personalizing
Therapy of PD
Cytochrome P450 CYP2D6 enzyme, which metabolizes many drugs, is also
involved in the metabolism of dopamine. In studies comparing PD patients exhibit-
ing side effects such as “on-off” phenomenon and dyskinesia (both suggesting
favorable response to therapy) with a subgroup of patients showing no such
response, only the prevalence of CYP2D6 4 allele was found to differ signifi cantly
between the PD patients and control group.
Response of individual patients to levodopa and adverse reactions vary consider-
ably. An understanding of the basis of these differential effects may enable modifi -
cation of the drug dose, or combination of levodopa with other drugs, to produce the
best outcome for individual patients and to avoid such reactions. There is a trend
now toward incorporating genetics into clinical studies of therapy for PD to inves-
tigate how a person’s genetic make-up infl uences the effect of drugs that work by
neurochemical intervention. Approximately 50 % of PD patients treated with
L-dopa develop L-dopa-induced dyskinesias in the long term, and the use of phar-
macogenetics should be explored in an effort to reduce this complication.
Discovery of Subgroup-Selective Drug Targets in PD
Global gene-expression profi les defi ne the four major classes of dopaminergic (DA)
and noradrenergic neurons in the brain. Molecular profi les provide a basis for
understanding the common and population-specifi c properties of catecholaminergic
(CA) neurons and will facilitate the development of selective drugs. One goal of
such studies is to identify genes that may infl uence the selective vulnerability of CA
neurons in PD. The substantia nigra (SN) is most susceptible to PD pathology,
whereas the adjacent ventral tegmental area (VTA) DA neurons are less vulnerable
and hypothalamic DA neurons are spared. The sparing of VTA neurons could be
mediated by selective expression of neuroprotective factors, including neurotrophic
factors, detoxifying enzymes, lipoprotein lipase, etc. There is selective high expres-
sion of γ-synuclein in neurons of the SN and in locus coeruleus noradrenergic neu-
rons that degenerate in PD, which may modify the toxic effects of the widely
expressed α-synuclein protein. Likewise, selective expression of the Zn 2+ trans-
porter by the SN and VTA may play a role in the pathophysiology of PD. Low
concentrations of Zn 2+ can exert a cell-protective effect; however, excess of Zn 2 2+
is neurotoxic and has been shown to promote degeneration of midbrain DA neurons.
Thus the molecular signatures of the major classes of CA neurons improve our
understanding of the characteristic features and functions of these neurons and
facilitate the discovery of subgroup-selective drug targets.
Personalized Management of Parkinson Disease