The pathological substrate is a neuronal loss predominantly of dopaminergic neurons of the substantia nigra, in the presence of characteristic eosinophilic inclusions, the Lewy bodies. The cause of most cases of PD is

still unknown, but both genetic and environmental factors arc thought to Doramapimod purchase contribute to the development of the disease. Genetic contributions to the etiology of PD were implicated in early descriptions of the disease.1 Later, the importance of genetic factors was thought to be low due to twin studies, which produced low concordance rates.2,3 However, in Inhibitors,research,lifescience,medical more recent years, interest in the genetics of PD has surged, as a consequence of the identification

of several monogenicaily inherited forms of the disease. The mapping and cloning of an increasing number of disease genes in Inhibitors,research,lifescience,medical these families has provided new insights into the pathogenesis of the disorder (Table I.)4-13 Table I. Genetically defined forms of Parkinson’s disease and parkinsonism. LB, Lewy body. Autosomal-dominant forms of PD Monogenic forms of PD with Inhibitors,research,lifescience,medical autosomal-dominant inheritance appear to be extremely rare. Nevertheless, the identification of disease-causing mutations has had a major impact on our understanding of the pathogenesis of PD. PARK1 α-Synuclein was the first PD gene to be identified as causing autosomal-dominant Inhibitors,research,lifescience,medical parkinsonism in a large ItalianAmerican family (Contursi kindred). The clinical picture was reported to be consistent with typical L-dopa-responsive PD with Lcwy body pathology, but with an unusually early onset (mean 44 years) and rapid disease progression. Inhibitors,research,lifescience,medical A point mutation (A53T) in the α-synuclein gene was found in this and several (probably related) Greek families.4 Two additional point mutations, A30P in a German family14 and E46K,15

were identified later. Although point, mutations in the α-synuclein gene appear to be a very rare cause of PD,16,17 this finding was of great importance because oc-synuclein was subsequently identified as the principle component of the Lewy body, which is also the pathological hallmark of typical sporadic PD. Consequently, the pathological Tryptophan synthase aggregation of α-synuclein is thought to play a central role in the molecular pathogenesis of PD. This was further substantiated by the recent finding of a triplication of a 2-Mb genomic region containing the α-synuclein gene in a large autosomal-dominant family with PD.7 This genomic aberration leads to an overcxprcssion of the intact α-synuclein gene, indicating the susceptibility of neurons to an overload with this amyloidogenic protein.