SNCA variants are associated with increased risk for multiple system atrophy

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Bethesda, MD 20892, USA.
Annals of Neurology (Impact Factor: 11.91). 05/2009; 65(5):610-4. DOI: 10.1002/ana.21685
Source: PubMed

ABSTRACT To test whether the synucleinopathies Parkinson's disease and multiple system atrophy (MSA) share a common genetic etiology, we performed a candidate single nucleotide polymorphism (SNP) association study of the 384 most associated SNPs in a genome-wide association study of Parkinson's disease in 413 MSA cases and 3,974 control subjects. The 10 most significant SNPs were then replicated in additional 108 MSA cases and 537 controls. SNPs at the SNCA locus were significantly associated with risk for increased risk for the development of MSA (combined p = 5.5 x 10(-12); odds ratio 6.2) [corrected].

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    ABSTRACT: α-Synuclein is an abundantly expressed neuronal protein that is at the center of focus in understanding a group of neurodegenerative disorders called α-synucleinopathies, which are characterized by the presence of aggregated α-synuclein intracellularly. Primary α-synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy, with α-synuclein also found secondarily in a number of other diseases, including Alzheimer's disease. Understanding how α-synuclein aggregates form in these different disorders is important for the understanding of its pathogenesis in Lewy body diseases. PD is the most prevalent of the α-synucleinopathies and much of the initial research on α-synuclein Lewy body pathology was based on PD but is also relevant to Lewy bodies in other diseases (dementia with Lewy bodies and Alzheimer's disease). Polymorphism and mutation studies of SNCA, the gene that encodes α-synuclein, provide much evidence for a causal link between α-synuclein and PD. Among the primary α-synucleinopathies, multiple system atrophy is unique in that α-synuclein deposition occurs in oligodendrocytes rather than neurons. It is unclear whether α-synuclein originates from oligodendrocytes or whether it is transmitted somehow from neurons. α-Synuclein exists as a natively unfolded monomer in the cytosol, but in the presence of lipid membranes it is thought to undergo a conformational change to a folded α-helical secondary structure that is prone to forming dimers and oligomers. Posttranslational modification of α-synuclein, such as phosphorylation, ubiquitination and nitration, has been widely implicated in α-synuclein aggregation process and neurotoxicity. Recent studies using animal and cell models, as well as autopsy studies of patients with neuron transplants, provided compelling evidence for prion-like propagation of α-synuclein. This observation has implications for therapeutic strategies, and much recent effort is focused on developing antibodies that target extracellular α-synuclein.
    Alzheimer's Research and Therapy 01/2014; 6(5):73. DOI:10.1186/s13195-014-0073-2 · 3.50 Impact Factor
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    ABSTRACT: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been reported to be responsible for autosomal dominant late-onset sporadic Parkinson's disease (PD). The R1628P and G2385R polymorphisms of the LRRK2 gene have been identified as exclusively associated with PD in Asian populations, particularly in Han Chinese population. Considering that there is overlap of the clinical manifestations and pathological characteristics between PD and MSA, we studied the possible associations between R1628P and G2385R polymorphisms of the LRRK2 and MSA in a population of Han Chinese patients.Methods and patientsA total of 318 MSA patients and 350 unrelated age- and sex-matched healthy controls (HCs) were included in the study. All subjects were genotyped for R1628P and G2385R using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis and direct sequencing.ResultsNo significant differences were observed in the genotype distribution and minor allele frequency (MAF) of R1628P between MSA patients and HCs (P = 0.418 and P = 0.424), between MSA-C and HCs (P = 0.347 and P = 0.353), between MSA-P and HCs (P = 0.787 and P = 0.790), and between MSA-C and MSA-P (P = 0.606 and P = 0.610). In addition, no significant differences were also observed in the genotype distribution and MAF of G2385R between MSA patients and HCs (P = 0.141 and P = 0.051), between MSA-C and HCs (P = 0.061 and P = 0.065), between MSA-P and HCs (P = 0.184 and P = 0.158), and between MSA-C and MSA-P (P = 0.354 and P = 0.853).Conclusion The present study suggests that R1628P and G2385R polymorphisms of the LRRK2 are not risk factors for MSA in the Han Chinese population.KeywordsMultiple system atrophyLRRK2R1628PG2385RChinese
    Parkinsonism & Related Disorders 12/2014; 21(2). DOI:10.1016/j.parkreldis.2014.11.022 · 4.13 Impact Factor
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    ABSTRACT: Multiple system atrophy (MSA) is a rare, late-onset and fatal neurodegenerative disease including multisystem neurodegeneration and the formation of α-synuclein containing oligodendroglial cytoplasmic inclusions (GCIs), which present the hallmark of the disease. MSA is considered to be a sporadic disease; however certain genetic aspects have been studied during the last years in order to shed light on the largely unknown etiology and pathogenesis of the disease. Epidemiological studies focused on the possible impact of environmental factors on MSA disease development. This article gives an overview on the findings from genetic and epigenetic studies on MSA and discusses the role of genetic or epigenetic factors in disease pathogenesis.
    12/2014; 23(4):277-91. DOI:10.5607/en.2014.23.4.277

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