Increased susceptibility to sporadic Parkinson's disease by a certain combined ?-synuclein/apolipoprotein E genotype

Abstract

Parkinson's disease (PD) is one of the most common neurodegenerative disorders affecting about 1% of Western populations older than age 50. The pathological hallmark of PD are Lewy bodies, that is, intracytoplasmic inclusion bodies in affected neurons of the substantia nigra. Recently, α‐synuclein (α‐SYN) has been identified as the main component of Lewy bodies in sporadic PD, suggesting involvement in neurodegeneration via protein accumulation. The partially overlapping pathology of PD and Alzheimer's disease, as well as striking structural similarities of α‐SYN and apolipoprotein E, which is a major risk factor for late‐onset Alzheimer's disease, prompted us to investigate the influence of different α‐SYN and apolipoprotein E alleles for developing sporadic PD. We performed association studies in 193 German PD patients and 200 healthy control subjects matched for age, sex, and origin. A polymorphism in the promoter region of the α‐SYN gene (NACP‐Rep1) as well as of the closely linked DNA markers D4S1647 and D4S1628 revealed significant differences in the allelic distributions between PD patients and the control group. Furthermore, the Apoε4 allele but not the Th1/E47 promoter polymorphism of the apolipoprotein E gene was significantly more frequent among early‐onset PD patients (age at onset, <50 years) than in late‐onset PD. Regarding the combination of the Apoε4 allele and allele 1 of the α‐SYN promoter polymorphism, a highly significant difference between the group of PD patients and control individuals has been found, suggesting interactions or combined actions of these proteins in the pathogenesis of sporadic PD. PD patients harboring this genotype have a 12.8‐fold increased relative risk for developing PD during their lives. Ann Neurol 1999;45:611–617

Transcriptional dysregulation in a transgenic model of Parkinson disease

“…Families with mutated α-syn exhibit autosomal dominant PD (Athanassiadou et al, 1999;Kruger et al, 1998;Polymeropoulos et al, 1997;Zarranz et al, 2004), and gene multiplication leading to increased wildtype α-syn levels also causes disease (Singleton et al, 2003). Certain α-syn promoter polymorphisms are PD risk factors, suggesting that even modest increases in expression can predispose to disease (Farrer et al, 2001;Kruger et al, 1999;Pals et al, 2004;Tan et al, 2000;Wang et al, 2006). In patients without genetic mutations, α-syn is found in Lewy bodies and degenerating neurites (Irizarry et al, 1998;Spillantini et al, 1997).…”

Polymorphism in candidate genes: implications for the risk and treatment of idiopathic Parkinson's disease

“…Four of them showed that the E4 allele occurred more often in demented 105,106 and nondemented 107,108 PD patients, but the others did not find any positive associations. 69, Two additional studies examined the C/G-T/A transition converting codon 158 from arginine (E3) to cysteine (E2), and found that E4 allele E4 had a higher frequency in young 131 and demented 132 PD patients. Taken together, the results of these studies raise doubts as to the association between Apo-E and PD risk.…”

“…Mutations of the alphasynuclein gene have been shown to be relevant in some rare cases of autosomal dominant PD. Among the nine association studies performed to date, only four found significant results for the polymorphism of the promoter region of the alpha-synuclein gene (NACP-Rep1) in German, 131 American, 150,151 and Japanese 152 populations; the remaining studies from Japan, 153 Ireland, 154 Singapore, 155 Germany, 156 and Italy 157 found no differences from controls. More studies and meta-analysis are needed in order to determine Polymorphism in dopamine-related genes Y Gilgun-Sherki et al unequivocally whether the alpha-synuclein gene polymorphism is associated with IPD risk (see also Table 1).…”

Allelic variation of serotonin transporter expression is associated with depression in Parkinson's disease

“…Rare forms of PD are transmitted in an autosomal dominant or autosomal recessive mode of inheritance: for these, mutations in the Park 1 locus (␣-synuclein) or the Park 2 locus have been demonstrated, while the underlying mutation in a third locus, Park 3, has not yet been identified. 1 The vast majority of PD cases, however, are sporadic and are probably caused by the interaction of several genes with multiple environmental factors. One of these genes may be the ⑀4 allele of the apolipoprotein E gene, which in conjunction with a Park 1 promoter polymorphism has very recently been shown to increase the risk for developing sporadic PD.…”

“…One of these genes may be the ⑀4 allele of the apolipoprotein E gene, which in conjunction with a Park 1 promoter polymorphism has very recently been shown to increase the risk for developing sporadic PD. 1 The most striking symptoms of PD relate to the motor system, with rigidity, tremor, and akinesia. However, psychiatric manifestations including depression and dementia syndrome are common in PD patients.…”