Genetic players in multiple system atrophy: unfolding the nature of the beast

Stemberger, Sylvia; Scholz, Sonja W.; Singleton, Andrew B.; Wenning, Gregor K.

doi:10.1016/j.neurobiolaging.2011.04.001

Cited by 41 publications

(40 citation statements)

References 101 publications

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“…Genetic research into MSA has so far been lagging behind that of related neurodegenerative diseases, such as PD, but recent studies suggest that genetic factors have a role in this disease [329]. To date the majority of genetic studies in MSA have screened candidate genes for coding mutations, including SNCA, MAPT, and other PD genes, but more recently, some association studies screening for common genetic variants in MSA have been reported, and a GWAS is currently in progress (see [330].…”

Section: It Improves Mitochondrial Dysfunction Altersmentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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Section: It Improves Mitochondrial Dysfunction Altersmentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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“…When MSA is in the differential diagnosis, genetic testing for the spinocerebellar ataxias in such patients is recommended to essentially rule out a familial ataxia. [25, 26]…”

Section: Clinical and Neuropathological Features Of Msamentioning

confidence: 99%

“…[1, 26] Despite this well-defined classification system of MSA, current treatment options for patients with either subtype is far from optimal: not only is there no treatment to delay the progression of disease, but levodopa is considered the primary treatment for symptoms, which has a “modest and non-sustained effect.”[28, 29] While approximately 30% of MSA patients demonstrate an initial response to levodopa therapy, this response does not persist although patients often find it hard to stop this drug. [30]…”

Section: Clinical and Neuropathological Features Of Msamentioning

confidence: 99%

“…[26] In particular, studies have suggested positive association between cytokine gene polymorphisms and MSA genetic vulnerability. 68 As cytokines are key players in immunity and inflammation, such findings are consistent with MSA as a neuroinflammatory process.…”

Section: What Is Known About the Genetics Of Msamentioning

confidence: 99%

“…[67] Thus, in order to further elucidate the inflammatory etiology underlying MSA pathophysiology and a potential association with CJD, additional studies to seek out (new and confirm previous) inflammatory marker associations are vital. [26]…”

Section: What Is Known About the Genetics Of Msamentioning

confidence: 99%

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Multiple system atrophy: the application of genetics in understanding etiology

Federoff

Schottlaender²,

Houlden³

et al. 2015

Clin Auton Res

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Classically defined phenotypically by a triad of cerebellar ataxia, parkinsonism and autonomic dysfunction in conjunction with pyramidal signs, multiple system atrophy (MSA) is a rare and progressive neurodegenerative disease affecting an estimated 3-4 per every 100,000 individuals among adults 50-99 years of age. With a pathological hallmark of alpha-synuclein-immunoreactive glial cytoplasmic inclusions (GCIs; Papp-Lantos inclusions), MSA patients exhibit marked neurodegenerative changes in the striatonigral and/or olivopontocerebellar structures of the brain. As a member of the alpha-synucleinopathy family, which is defined by its well-demarcated alpha-synuclein-immunoreactive inclusions and aggregation, MSA’s clinical presentation exhibits several overlapping features with other members including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Given the extensive fund of knowledge regarding the genetic etiology of PD revealed within the past several years, a genetic investigation of MSA is warranted. While a current genome wide association (GWA) study is underway for MSA to further clarify the role of associated genetic loci and single nucleotide polymorphisms (SNPs), several cases have presented solid preliminary evidence of a genetic etiology. Naturally, genes and variants manifesting known associations with PD (and other phenotypically similar neurodegenerative disorders), including SNCA and MAPT, have been comprehensively investigated in MSA patient cohorts. More recently variants in COQ2 have been linked to MSA in the Japanese population although this finding awaits replication. Nonetheless, significant positive associations with subsequent independent replication studies have been scarce. With very limited information regarding genetic mutations or alterations in gene dosage as a cause of MSA, the search for novel risk genes, which may be in the form of common variants or rare variants, is the logical nexus for MSA research. We believe that the application of next generation genetic methods to MSA will provide valuable insight into the underlying causes of this disease, and will be central to the identification of etiologic based therapies.

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