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: 9.98). 05/2009; 65(5):610-4. DOI: 10.1002/ana.21685
Source: PubMed


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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Available from: Reema Paudel
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    • "So far, no SNCA mutations were reported for MSA, while a MSA-like phenotype was described in one case with SNCA duplication (Fuchs et al., 2007). Several polymorphisms at the SNCA locus were linked to both idiopathic PD and MSA (Al-Chalabi et al., 2009; Nalls et al., 2011; Scholz et al., 2009). Additional polymorphisms of the tau gene and others were identified for PD, but not for MSA which could either be related to different pathogenesis or to the insufficient power of the MSA studies due to the small number of included patients. "
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    ABSTRACT: Despite active fundamental, translational and clinical research, no therapeutic intervention has yet shown convincing effects on disease progression in Parkinson's disease (PD) patients. Indeed, several disease-modification trials failed or proved to be inconclusive due to lack of consistency between clinical rating scales and putative surrogate markers of disease progression, or confounding symptomatic effects of the tested compound. Multiple system atrophy (MSA) is a rapidly progressing orphan disorder leading to severe motor disability within a few years. Together with PD and dementia with Lewy bodies (DLB), MSA belongs to the synucleinopathies, a group of neurodegenerative disorders characterized by the abnormal accumulation of alpha-synuclein. Crucial milestones have been reached for successfully conducting clinical intervention trials in a large number of patients with MSA. In this personal view, we will review evidence, and discuss why MSA could prove the most relevant clinical model for assessing treatments that target mechanisms operating in all synucleinopathies.
    Full-text · Article · Jul 2014 · Neurobiology of Disease
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    • "A number of studies have shown that the A30P α-syn mutant associated with familial PD displays defective binding to lipid membranes, while the A53T mutant shows no such difference compared to wild-type protein [18,48,49]. Although there are no known causative α-syn mutations in MSA, variants of the SNCA gene have been identified to be associated with an increased risk for MSA [11,50]. "
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    ABSTRACT: Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by the accumulation of alpha-synuclein protein in the cytoplasm of oligodendrocytes, the myelin-producing support cells of the central nervous system (CNS). The brain is the most lipid-rich organ in the body and disordered metabolism of various lipid constituents is increasingly recognized as an important factor in the pathogenesis of several neurodegenerative diseases. alpha-Synuclein is a 17 kDa protein with a close association to lipid membranes and biosynthetic processes in the CNS, yet its precise function is a matter of speculation, particularly in oligodendrocytes. alpha-Synuclein aggregation in neurons is a well-characterized feature of Parkinson's disease and dementia with Lewy bodies. Epidemiological evidence and in vitro studies of alpha-synuclein molecular dynamics suggest that disordered lipid homeostasis may play a role in the pathogenesis of alpha-synuclein aggregation. However, MSA is distinct from other alpha-synucleinopathies in a number of respects, not least the disparate cellular focus of alpha-synuclein pathology. The recent identification of causal mutations and polymorphisms in COQ2, a gene encoding a biosynthetic enzyme for the production of the lipid-soluble electron carrier coenzyme Q10 (ubiquinone), puts membrane transporters as central to MSA pathogenesis, although how such transporters are involved in the early myelin degeneration observed in MSA remains unclear. The purpose of this review is to bring together available evidence to explore the potential role of membrane transporters and lipid dyshomeostasis in the pathogenesis of alpha-synuclein aggregation in MSA. We hypothesize that dysregulation of the specialized lipid metabolism involved in myelin synthesis and maintenance by oligodendrocytes underlies the unique neuropathology of MSA.
    Full-text · Article · Feb 2014
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    • "MSA is rarely familial (Soma et al., 2006) and mutations in a-synuclein have not been observed (Ozawa et al., 2006). However , polymorphisms in the synuclein gene may influence susceptibility to MSA (Al-Chalabi et al., 2009; Scholz et al., 2009). "
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    ABSTRACT: Human genetics has indicated a causal role for the protein α-synuclein in the pathogenesis of familial Parkinson's disease (PD), and the aggregation of synuclein in essentially all patients with PD suggests a central role for this protein in the sporadic disorder. Indeed, the accumulation of misfolded α-synuclein now defines multiple forms of neural degeneration. Like many of the proteins that accumulate in other neurodegenerative disorders, however, the normal function of synuclein remains poorly understood. In this article, we review the role of synuclein at the nerve terminal and in membrane remodeling. We also consider the prion-like propagation of misfolded synuclein as a mechanism for the spread of degeneration through the neuraxis.
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