Ž . European Journal of Pharmacology 413 2001 11–29 www.elsevier.nlrlocaterejphar Review Pharmacogenomics of neurodegenerative diseases Davide Maimone a , Roberto Dominici b , Luigi M.E. Grimaldi b,c, ) a Department of Neurology, Ospedale Garibaldi, Piazza S. Maria di Gesu 5, 95123 Catania, Italy ` b Istituto Scientifico San Raffaele, Dipartimento di Neuroscienze, Via Olgettina 58, 20132 Milan, Italy c Centro Studi Memoria e Demenze, Dipartimento di Neuroscienze, AUSL 2 Regione Siciliana, Via Cusmano 3, 93100 Caltanissetta, Italy Received 1 November 2000; received in revised form 30 November 2000; accepted 5 December 2000 Abstract Current knowledge of sporadic degenerative disorders suggests that, despite their multifactorial etiopathogenesis, genetics plays a primary role in orchestrating the pathological events, and even dramatically changes the disease phenotype from patient to patient. Genes may act as susceptibility factors, increasing the risk of disease development, or may operate as regulatory factors, modulating the magnitude and severity of pathogenic processes or the response to drug treatment. The goal of pharmacogenomics is the application of this knowledge to elaborate more specific and effective treatments and to tailor therapies to individual patients according to their genetic profile. Here, we outline the leading theories on the etiopathogenesis of neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer disease, and we review the potential role of genetic variations, such as gene mutations and polymorphisms, in each context. We also suggest potential targets for new therapeutic approaches and variability factors for current treatments based on genotype features. Finally, we propose a few options of preventive therapeutic interventions in patients with a high genetic risk of disease. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Amyotrophic lateral sclerosis; Parkinson disease; Alzheimer disease; Gene polymorphism; Gene mutation; Pharmacogenomics 1. Introduction The deciphering of the human genome means the vir- tual end of an age of human genomics aimed at the localization of genes on the chromosomal material. Al- ready heralded by a few pioneering studies, a new era of post-genomics genotype–phenotype correlations has started. In the future, researchers will attempt to correlate genes with functions, assess polymorphic variations of these activities in the various populations and determine their impact on physiological and pathological conditions. If the number of genes is in the 80.000–100.000 range, the investigation of the role played by each of these genes in human diseases, and the role of reciprocal interactions, is likely to require the work of several generations of re- searchers. A particular aspect of this variability is the goal of A Pharmacogenomics B, i.e. a field of research devoted to ) Corresponding author. Deparment of Neurology, University of Mi- lano, San Raffaele Scientific Institute, Neuroimmunology Unit—DIBIT, Via Olgettina 58, 20132, Milano, Italy. Tel.: q 39-02-2643-4867; fax: q 39-02-2643-4855. Ž . E-mail address: luigi.grimaldi@hsr.it L.M.E. Grimaldi . understanding how genetic factors can direct the choice of selective therapies and influence the response to estab- lished treatments for human diseases. Treatments normally entail the interaction between an exogenously administered Ž . stimulus protein, radiation, etc. and a number of endoge- nous proteins involved in the pathogenesis of the disease. A typical interaction occurs between the receptor for a neurotransmitter and an exogenous molecule able to block this interaction. By definition, all the genes coding for these proteins are polymorphic: Mendelian mutations or allelic variations in their sequence could account for the phenotypic variability in the response to present or future therapies. In theory, any gene can affect any given clinical feature of a disease, and the majority of the genes code for still unidentified proteins. As such, it is impossible to predict which gene will be pivotal in determining the response to a given therapy. The only way to sort out these interactions is to assess them under specifically designed experimental conditions. When applied to neurodegenerative diseases, pharma- cogenomics is still in its infancy. In fact, the etiopatho- genetic mechanisms underlying most of these illnesses are still poorly understood, which makes the search for the genes whose variability may account for the differential 0014-2999r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. Ž . PII: S0014-2999 00 00939-0