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Parkinson’s disease is the most common neurodegenerative disorder after Alzheimer’s disease, preferentially affecting locomotor activities of elderly people. Although our knowledge concerning the pathogenesis of Parkinson’s disease is still limited, some environmental toxins have been postulated as candidate substances which accelerate dopaminergic neuronal death through impaired cellular metabolism, such as mitochondrial oxidative dysfunction or excessive effects of free radicals. However, there has been increasing evidence suggesting that genetic factors may play some part in the pathophysiological processes of this disease. For example, studies using PET indicated a significantly higher concordance rate for decreased striatal [18F] dopa uptake in monozygotic twins.1 Furthermore, recent complex clinical analyses, aimed at re-evaluating family histories of cases of Parkinson’s disease, showed a significantly higher incidence of parkinsonian symptoms among relatives. These findings suggest autosomal dominant inheritance of the disease.2 Under these circumstances, several genes have been proposed as candidate genes for Parkinson’s disease.3 However, the association of these candidate genes with the disease is still controversial.
Several large, multigeneration families with parkinsonism have been described. Among them, the Italian autosomal dominantly inherited pedigree reported by Golbe et al 4 and Polymeropoulos et al 5 has received attention because clinical features are similar to those of sporadic Parkinson’s disease. Although the mean age at onset of the illness is somewhat earlier, each affected person in this pedigree closely resembles a case with idiopathic Parkinson’s disease in clinical symptoms and therapeutic effectiveness of levodopa. Moreover, as in idiopathic Parkinson’s disease, there are some variations in initial symptoms among the affected members of the family. For example, some presented with rest tremor, bradykinesia, and rigidity, whereas others presented with an akinetic rigid symptom, but without tremor. In addition, postmortem examination showed pathological changes with Lewy bodies, mimicking those of idiopathic Parkinson’s disease. In this pedigree, it has been recently reported that genetic markers on chromosome 4q21-q23 (D4S2380 and D4S1647) are linked to the parkinsonism.5 Here, we investigated a possible relation of the genetic marker D4S1647 to Japanese idiopathic Parkinson’s disease by allelic association study.
We studied 111 patients with sporadic Parkinson’s disease (age 64.6 (SD 9.7) range 35–81), diagnosed by a combination of three of the following neurological features: tremor, rigidity, bradykinesia, and postural instability. Levodopa therapy was effective in all patients. Cases of secondary parkinsonism due to other neurological diseases, chemicals, or toxins were excluded. One hundred and two patients (age 69.0 (SD 10.1); range 47–95) with old cerebrovascular disease were chosen as age matched controls, because we could strictly exclude Parkinson’s disease in these cases. All subjects were Japanese. Genomic DNAs were extracted from leucocytes by conventional procedures. The region containing the genetic marker D4S1647, consisting of ATAG tetranucleotide repeats on chromosome 4q21-q23, was amplified by polymerase chain reaction (PCR). The PCR assays were performed with 27 cycles of denaturation at 94°C for 30 seconds, annealing at 55°C for 75 seconds, and extension at 72°C for 15 seconds, followed by a final extension at 72°C for six minutes. A fluorescence labelled primer p1(5′-TATTTCCAACACCCCTGCTA-3′) and an unlabelled antisense primer p2 (5′-AAGCAAAGAGGATTGAAAGTG-3′) were designed according to the Genome Data Base (http://gdbwww.gdb.org) and the Cooperative Human Linkage Consortium database (http://www.chlc.org). The PCR products were analysed with a laser based automated DNA sequencer (Pharmacia). Allele frequencies were statistically compared between Parkinson’s disease and controls using Bonferroni’s method.
The table shows the allele frequencies of each group. The (ATAG)9 allele is the most common in the Japanese population. There were no significant differences in allele frequencies between patients with Parkinson’s disease and controls. Another common neurodegenerative disease, Alzheimer’s disease, also consists of inherited and non-inherited cases. The existence of several familial Alzheimer’s disease pedigrees prompted us to elucidate several genes responsible for the pathogenesis. Clinical and pathological features of these patients with familial Alzheimer’s disease are similar to those of patients with sporadic disease, and recent data on the responsible genes have greatly contributed to our comprehensive understanding of the common neurodegenerative processes, which may occur in both familial and sporadic Alzheimer’s disease. The ApoE ε4 allele has been shown to be associated not only with late onset familial Alzheimer’s disease but also with sporadic disease.6 The Parkinson’s disease phenotype, linked to chromosome 4q21-q23, showed a high degree of penetrance and therefore it is not plausible that the same mutation is also responsible for idiopathic Parkinson’s disease. However, other possible mutations in the same responsible gene may associate with milder clinical manifestations and a low degree of penetrance, mimicking idiopathic Parkinson’s disease. Although this microsatellite is not a very informative marker because of low genetic variation and our results could not show a direct relation between familial and idiopathic Parkinson’s disease, the discovery of this novel candidate locus opens up a new avenue for elucidating a putative common pathway responsible for “Lewy body type” neurodegeneration.
Polymeropoulos et al recently identified a mutation in the α-synuclein gene in this locus (Science 1997;276:2045–7).
This work was supported in part by an Inoue Research Award for Young Scientists from the Inoue Foundation for Science.
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