Lewy body extracts from Parkinson disease brains trigger α‐synuclein pathology and neurodegeneration in mice and monkeys

Recasens, Ariadna; Dehay, Benjamin; Bové, Jordi; Carballo‐Carbajal, Iria; Doveró, Sandra; Pérez-Villalba, Ana; Fernagut, Pierre‐Olivier; Blesa, Javier; Parent, Annabelle; Perier, Céline; Fariñas, Isabel; Obeso, José A.; Bézard, Erwan; Vila, Miquel

doi:10.1002/ana.24066

Cited by 564 publications

(575 citation statements)

References 43 publications

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“…Subsequently, in vitro and in vivo studies confirmed the ability of aSyn to be released/secreted and taken up by neighboring cells (18)(19)(20), further supporting the prion-like spreading of aSyn.…”

Section: Significancementioning

confidence: 74%

“…Because the application of The assignments are represented in percentage and were attributed to each peak observed according to Susi and Byler (75). pathological aSyn species has been reported to induce a glial response in vivo (20,36), we investigated the state of the astrocytes by probing for glial fibrillary acidic protein (GFAP). An increase in GFAP levels could only be detected in cells exposed to WT -Cu 2+ and H50Q -Cu 2+ , likely because of the development of reactive astrocytes, as GFAP staining revealed a phenotype compatible with reactive astrocytes (37) (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Villar‐Piqué

Fonseca

Sant’Anna

et al. 2016

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

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Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.α-synuclein | copper | H50Q mutation | inclusions | protein aggregation

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Section: Significancementioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Villar‐Piqué

Fonseca

Sant’Anna

et al. 2016

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

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“…Our ability to now synchronously and rapidly induce a motor phenotype and αS pathology by a peripheral injection of αS may prove invaluable in future studies exploring mechanisms of pathology induction and αS toxicity and may extend recent studies showing rapid induction following intracerebral inoculation (21)(22)(23)(24)(25)(26). Our finding that disease onset in M83 Tg mice can be shortened, predicted, and synchronized through a simple manipulation provides a valuable model to accelerate studies designed to fully understand the mechanisms underlying induction of the inclusion pathology and motor phenotype, but also to enable much more rapid and cost-effective preclinical testing of novel PD therapies.…”

Section: Discussionmentioning

confidence: 96%

“…And it has been suggested that αS pathology might originate in the nerves of the PNS and spread to the CNS (14). Experimentally, it has been reported that intracerebral injections of preformed amyloidogenic αS fibrils in nontransgenic (nTg) and αS transgenic (Tg) mice induce the formation of intracellular αS inclusions that appear to progress from the site of injection (21)(22)(23)(24)(25)(26). Collectively, these studies support the notion that αS inclusion pathology may propagate via a prion-like conformational self-templating mechanism (27,28).…”

mentioning

confidence: 99%

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

Sacino¹,

Brooks²,

Thomas³

et al. 2014

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

293

343

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It has been hypothesized that α-synuclein (αS) misfolding may begin in peripheral nerves and spread to the central nervous system (CNS), leading to Parkinson disease and related disorders. Although recent data suggest that αS pathology can spread within the mouse brain, there is no direct evidence for spread of disease from a peripheral site. In the present study, we show that hind limb intramuscular (IM) injection of αS can induce pathology in the CNS in the human Ala53Thr (M83) and wild-type (M20) αS transgenic (Tg) mouse models. Within 2-3 mo after IM injection in αS homozygous M83 Tg mice and 3-4 mo for hemizygous M83 Tg mice, these animals developed a rapid, synchronized, and predictable induction of widespread CNS αS inclusion pathology, accompanied by astrogliosis, microgliosis, and debilitating motor impairments. In M20 Tg mice, starting at 4 mo after IM injection, we observed αS inclusion pathology in the spinal cord, but motor function remained intact. Transection of the sciatic nerve in the M83 Tg mice significantly delayed the appearance of CNS pathology and motor symptoms, demonstrating the involvement of retrograde transport in inducing αS CNS inclusion pathology. Outside of scrapie-mediated prion disease, to our knowledge, this findiing is the first evidence that an entire neurodegenerative proteinopathy associated with a robust, lethal motor phenotype can be initiated by peripheral inoculation with a pathogenic protein. Furthermore, this facile, synchronized rapid-onset model of α-synucleinopathy will be highly valuable in testing disease-modifying therapies and dissecting the mechanism(s) that drive αS-induced neurodegeneration.amyloid | Parkinson disease S ynucleinopathies are a group of diseases defined by the presence of amyloidogenic α-synuclein (αS) inclusions that can occur in neurons and glia of the central nervous system (CNS) (1-4). In Parkinson disease (PD), a causative role for αS has been established via the discovery of mutations in the αS gene SNCA resulting in autosomal-dominant PD (4-11). Although αS inclusions (e.g., Lewy bodies) are the hallmark pathology of PD, how they contribute to disease pathogenesis remains controversial (1,3,4,12).Postmortem studies have suggested that αS pathology may spread following neuroanatomical tracts (13-15) and between cells (16-18). αS pathology has also been found in the peripheral nervous system (PNS): for example, in the enteric and pelvic plexus (19,20). And it has been suggested that αS pathology might originate in the nerves of the PNS and spread to the CNS (14). Experimentally, it has been reported that intracerebral injections of preformed amyloidogenic αS fibrils in nontransgenic (nTg) and αS transgenic (Tg) mice induce the formation of intracellular αS inclusions that appear to progress from the site of injection (21-26). Collectively, these studies support the notion that αS inclusion pathology may propagate via a prion-like conformational self-templating mechanism (27, 28). A caveat of the direct intracerebral injection of αS is tha...

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“…The next step was to move from mice to non human primates. In 2014, a team at the University of Barcelona in Spain injected Lewy bodies extracted from human brains into the substantia nigra and striatum of four macaque monkeys 8 . Over 14 months the researchers observed gradual neuronal degeneration, first of the long axons that extend from neurons in the substantia nigra to the striatum, then of the substantia nigra neurons themselves.…”

Section: Pursuing Proofmentioning

confidence: 99%

Pathology: The prion principle

Makin¹

2016

Nature

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A controversial theory that could revolutionize our understanding of Parkinson's disease is gaining ground. But not everybody is convinced that misfolded proteins that spread in the brain are the cause of the disease. LYSIA FORNO/SPLTransmission electron micrograph of a Lewy body, which is made of misfolded α-synuclein protein.© 2 0 1 6 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .

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Lewy body extracts from Parkinson disease brains trigger α‐synuclein pathology and neurodegeneration in mice and monkeys

Cited by 564 publications

References 43 publications

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

Pathology: The prion principle

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