A novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology

Pasanen, Petra; Myllykangas, Liisa; Siitonen, Maija; Raunio, Anna; Kaakkola, Seppo; Lyytinen, Jukka; Tienari, Pentti J.; Pöyhönen, Minna; Paetau, Anders

doi:10.1016/j.neurobiolaging.2014.03.024

Cited by 428 publications

(360 citation statements)

References 23 publications

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“…Because inherited cases have been identified in all neurodegenerative diseases, we asked if any of the MSA or PD samples contained either a mutant α-synuclein (SNCA) or COQ2 gene. Duplications, triplications, and missense mutations in SNCA have been identified in a minority of patients with PD (20); SNCA single nucleotide polymorphisms (SNPs) are associated with MSA risk (21); and, recently, novel SNCA mutations were reported in cases with mixed MSA and PD pathology (22)(23)(24). In addition, an investigation of familial MSA identified coenzyme Q10, specifically the COQ2 gene, to be associated with MSA in two families (25).…”

Section: Resultsmentioning

confidence: 99%

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism

Prusiner

Woerman

Mordes

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

645

677

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Prions are proteins that adopt alternative conformations that become self-propagating; the PrPSc prion causes the rare human disorder Creutzfeldt–Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T–YFP) and TgM83+/− mice expressing α-synuclein (A53T). The TgM83+/− mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83+/+ mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83+/− mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T–YFP in cultured cells, whereas none of six Parkinson’s disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83+/+ mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.

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Section: Resultsmentioning

confidence: 99%

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism

Prusiner

Woerman

Mordes

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

645

677

View full text Add to dashboard Cite

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“…The main histopathological feature of PD is the formation of intracellular inclusions called Lewy bodies (LBs) that form as a result of the fibrillization of the presynaptic protein ␣-synuclein (␣-syn). Several point mutations in the gene coding for ␣-syn (SNCA) were identified and linked to the autosomal dominant inherited form of PD as follows: A53T (2-4), A30P (5), E46K (6), and recently H50Q (7,8), G51D (9), and A53E (10). Therefore, a better understanding of the mechanisms by which these mutations alter the physiological and pathogenic properties of ␣-syn could provide critical insights into the molecular basis underlying the pathogenesis of PD, and aid in the development of strategies to treat or prevent the disease.…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Parkinson Disease Mutant E46K Enhances α-Synuclein Phosphorylation in Mammalian Cell Lines, in Yeast, and in Vivo

Mbefo

Fares

Paleologou

et al. 2015

Journal of Biological Chemistry

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Background:Little is known about the effect of PD-linked mutations on ␣-synuclein (␣-syn) phosphorylation. Results: The E46K mutation increases ␣-syn phosphorylation at Ser-129 and influences its subcellular localization in vivo. Conclusion: The E46K mutation alters ␣-syn localization and post-translational modifications. Significance: PD-linked ␣-syn mutations may contribute to PD via different mechanisms.

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“…␣S pathological inclusions, which are also termed Lewy bodies or Lewy neurites, predominantly occur in neurons and are a defining feature of Parkinson's disease (PD) (1)(2)(3)(4)(5)(6)(7), but in other diseases such as multiple system atrophy, they can predominantly occur in oligodendrocytes (6,(8)(9)(10). A direct role for ␣S in neurodegeneration was established by the discovery of several genetic alterations in the ␣S gene (SNCA), in the form of missense mutations or increased copy number, which result in autosomal-dominant PD or the related disease, dementia with Lewy bodies (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Robust Central Nervous System Pathology in Transgenic Mice following Peripheral Injection of α-Synuclein Fibrils

Ayers

Brooks

Rutherford

et al. 2017

J Virol

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Misfolded ␣-synuclein (␣S) is hypothesized to spread throughout the central nervous system (CNS) by neuronal connectivity leading to widespread pathology. Increasing evidence indicates that it also has the potential to invade the CNS via peripheral nerves in a prion-like manner. On the basis of the effectiveness following peripheral routes of prion administration, we extend our previous studies of CNS neuroinvasion in M83 ␣S transgenic mice following hind limb muscle (intramuscular [i.m.]) injection of ␣S fibrils by comparing various peripheral sites of inoculations with different ␣S protein preparations. Following intravenous injection in the tail veins of homozygous M83 transgenic (M83 ϩ/ϩ ) mice, robust ␣S pathology was observed in the CNS without the development of motor impairments within the time frame examined. Intraperitoneal (i.p.) injections of ␣S fibrils in hemizygous M83 transgenic (M83 ϩ/Ϫ ) mice resulted in CNS ␣S pathology associated with paralysis. Interestingly, injection with soluble, nonaggregated ␣S resulted in paralysis and pathology in only a subset of mice, whereas soluble Δ71-82 ␣S, human ␤S, and keyhole limpet hemocyanin (KLH) control proteins induced no symptoms or pathology. Intraperitoneal injection of ␣S fibrils also induced CNS ␣S pathology in another ␣S transgenic mouse line (M20), albeit less robustly in these mice. In comparison, i.m. injection of ␣S fibrils was more efficient in inducing CNS ␣S pathology in M83 mice than i.p. or tail vein injections. Furthermore, i.m. injection of soluble, nonaggregated ␣S in M83 ϩ/Ϫ mice also induced paralysis and CNS ␣S pathology, although less efficiently. These results further demonstrate the prion-like characteristics of ␣S and reveal its efficiency to invade the CNS via multiple routes of peripheral administration. IMPORTANCEThe misfolding and accumulation of ␣-synuclein (␣S) inclusions are found in a number of neurodegenerative disorders and is a hallmark feature of Parkinson's disease (PD) and PD-related diseases. Similar characteristics have been observed between the infectious prion protein and ␣S, including its ability to spread from the peripheral nervous system and along neuroanatomical tracts within the central nervous system. In this study, we extend our previous results and investigate the efficiency of intravenous (i.v.), intraperitoneal (i.p.), and intramuscular (i.m.) routes of injection of ␣S fibrils and other protein controls. Our data reveal that injection of ␣S fibrils via these peripheral routes in ␣S-overexpressing mice are capable of inducing a robust ␣S pathology and in some cases cause paralysis. Furthermore, soluble, nonaggregated ␣S also induced ␣S pathology, albeit with much less efficiency. These findings further support and extend the idea of ␣S neuroinvasion from peripheral exposures.

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A novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology

Cited by 428 publications

References 23 publications

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism

Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism

Parkinson Disease Mutant E46K Enhances α-Synuclein Phosphorylation in Mammalian Cell Lines, in Yeast, and in Vivo

Robust Central Nervous System Pathology in Transgenic Mice following Peripheral Injection of α-Synuclein Fibrils

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