Prion-like acceleration of a synucleinopathy in a transgenic mouse model

Mougenot, Anne-Laure; Nicot, Simon; Bencsik, Anna; Morignat, Eric; Verchère, Jérémy; Lakhdar, Latefa; Legastelois, Stéphane; Baron, Thierry

doi:10.1016/j.neurobiolaging.2011.06.022

Cited by 345 publications

(340 citation statements)

References 7 publications

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“…In both cases, αS pathology is associated with a rapidly progressive motor phenotype that is subtly distinct from that in untreated, aged M83 Tg mice due to the initial foot drop presentation and the heightened neuroinflammatory response. From our findings, IM injections appear to induce a more rapid lethal motor phenotype (50-120 d incubation time) than reported in some studies where either homozygous or hemizygous M83 Tg were intracerebrally inoculated with CNS extracts from symptomatic M83 Tg (∼200 d incubation time) (23,24). However, Luk et al (21) reported that, in similar M83 Tg CNS extract transmission studies or with intracerebral injection of recombinant fib αS in homozygous M83 Tg mice, the incubation time to cause motor impairments was closer to what we observed resulting from IM injection of fib αS (i.e., ∼100 d) (21).…”

Section: Discussionmentioning

confidence: 42%

“…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).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 42%

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

View full text Add to dashboard Cite

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“…14,18,[21][22][23][24] Recent observations that the transplants grafted into the brain of PD patients displayed Lewy bodies 25,26 were considered to be connected with Braak et al's proposal that Lewy body pathology spreads from one brain area to another according to a stereotypic pattern in specific stages. 27 Consequently, more recent in vitro and in vivo experiments [28][29][30][31][32][33] have shown that α-syn aggregates released from neuronal cells can be transferred to neighboring neurons and form Lewy body-like inclusions, providing a mechanistic basis for the spread of α-syn pathology in PD patients and a hypothesis that a prion-like mechanism may underlie the progression of PD.…”

Section: Proteolytic Clearance As a Therapeutic Approach Against Pd Amentioning

confidence: 99%

Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease

Park

Kim

2013

Prion

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“…However, it is unclear to what extent they are self-propagating in a prion-like manner (220)(221)(222)(223)(224). In vivo studies of intracerebral injections of aggregated α-synuclein in transgene animal models with α-synuclein mutations have further shown accelerated occurrence of protein aggregation, followed by nigral loss and motor deficits, not present to the similar extent in wild type (WT) animals (225)(226)(227). Thus, exogenous seeds of α-synuclein may accelerate the pathogenesis of a genetically predisposed α-synuclein aggregation disease.…”

Section: Pd As a Prion Diseasementioning

confidence: 99%

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

et al. 2011

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Prion-like acceleration of a synucleinopathy in a transgenic mouse model

Cited by 345 publications

References 7 publications

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

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

Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

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