Brain Injection of α-Synuclein Induces Multiple Proteinopathies, Gliosis, and a Neuronal Injury Marker

Sacino, Amanda N.; Brooks, Michael C.; McKinney, Alex B.; Thomas, M. Albert; Shaw, Gerry; Golde, Todd E.; Giasson, Benoit I.

doi:10.1523/jneurosci.2102-14.2014

Cited by 117 publications

(133 citation statements)

References 79 publications

(40 reference statements)

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“…M20 ␣S Tg mice were generated similarly to the M83 line with the mouse prion protein promoter driving expression, but they express wild-type human ␣S rather than human ␣S containing the A53T mutation (41). Additionally, they express similar or higher levels of human ␣S with neuroanatomical distribution similar to that of M83 mice, but they never intrinsically develop a motor impairment phenotype or ␣S inclusion pathology (37,41,49). None of the M20 ϩ/Ϫ i.p.…”

Section: Resultsmentioning

confidence: 99%

“…injection of Δ71-82 ␣S, which lacks the ability to form fibrils or seed ␣S amyloid in vitro and in cultured cells under relatively physiologic conditions (42)(43)(44)(45), is more difficult to be explained by a conformational templating mechanism. Cerebral injections of Δ71-82 ␣S were previously shown to also have the ability to induce ␣S pathology in ␣S Tg mice, although with less efficiency than ␣S fibs (36,37). However, the possibility that in vivo, a small amount of exogenous Δ71-82 ␣S might spontaneously acquire amyloidogenic properties over time cannot be excluded, since under nonphysiological conditions (i.e., the presence of SDS), it can be artificially induced to form amyloid fibrils (51).…”

Section: Discussionmentioning

confidence: 99%

“…Using either human or mouse brain lysates containing ␣S aggregates or recombinant preformed ␣S fibrils (␣S fibs), it was reported that the brain injection of these preparations could result in the progressive induction of ␣S pathology in ␣S transgenic (Tg) mice and in some studies in nontransgenic (nTg) mice (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). However, we have recently reported that the studies using CNS homogenates can be confounded by a non-␣S factor enriched in the white matter that can induce similar ␣S pathology in ␣S Tg mice (39).…”

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confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…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%

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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“…Moreover, it is consistent with literature reports demonstrating that the propagation and spreading of α-Syn pathology is prominent when the injected PFFs and host-expressed monomers are from the same species. In most of these studies, seeding and spreading of α-Syn pathology was observed when mα-Syn PFFs were injected into non-Tg mice expressing mα-Syn (40)(41)(42) or when hα-Syn PFFs were injected into Tg mice expressing human α-Syn protein (43)(44)(45)(46)(47)(48)). …”

Section: Discussionmentioning

confidence: 99%

Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson’s disease

Fares

Maco

Oueslati

et al. 2016

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

104

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Lewy bodies (LBs) are intraneuronal inclusions consisting primarily of fibrillized human α-synuclein (hα-Syn) protein, which represent the major pathological hallmark of Parkinson's disease (PD). Although doubling hα-Syn expression provokes LB pathology in humans, hα-Syn overexpression does not trigger the formation of fibrillar LB-like inclusions in mice. We hypothesized that interactions between exogenous hα-Syn and endogenous mouse synuclein homologs could be attenuating hα-Syn fibrillization in mice, and therefore, we systematically assessed hα-Syn aggregation propensity in neurons derived from α-Syn-KO, β-Syn-KO, γ-Syn-KO, and triple-KO mice lacking expression of all three synuclein homologs. Herein, we show that hα-Syn forms hyperphosphorylated (at S129) and ubiquitin-positive LB-like inclusions in primary neurons of α-Syn-KO, β-Syn-KO, and triple-KO mice, as well as in transgenic α-Syn-KO mouse brains in vivo. Importantly, correlative light and electron microscopy, immunogold labeling, and thioflavin-S binding established their fibrillar ultrastructure, and fluorescence recovery after photobleaching/photoconversion experiments showed that these inclusions grow in size and incorporate soluble proteins. We further investigated whether the presence of homologous α-Syn species would interfere with the seeding and spreading of α-Syn pathology. Our results are in line with increasing evidence demonstrating that the spreading of α-Syn pathology is most prominent when the injected preformed fibrils and host-expressed α-Syn monomers are from the same species. These findings provide insights that will help advance the development of neuronal and in vivo models for understanding mechanisms underlying hα-Syn intraneuronal fibrillization and its contribution to PD pathogenesis, and for screening pharmacologic and genetic modulators of α-Syn fibrillization in neurons.Parkinson's disease | alpha-synuclein | aggregation T he aggregation of proteins into fibrillar structures is a key hallmark of many neurodegenerative disorders. In Parkinson's disease (PD), α-synuclein (α-Syn), a predominantly presynaptic protein involved in the regulation of neurotransmitter release, abnormally fibrilizes and forms intraneuronal inclusions termed "Lewy bodies" (LBs) (1, 2). So far, the mechanisms underlying LB formation remain poorly understood, and the impact of LB presence on neuronal viability remains controversial, in part due to the lack of animal models recapitulating α-Syn fibrillization into LB-like inclusions in the brain.Because patients with familial history of parkinsonism were found carrying either multiplications or point mutations of the α-Syn gene SNCA (2), most animal models of PD have been generated by overexpressing WT human α-Syn (hα-Syn) or mutant forms linked to familial PD (3). Strikingly, although rodent models expressing hα-Syn do not recapitulate the formation of fibrillar LBs within dopaminergic neurons, hα-Syn overexpression in Drosophila led to dramatic neuronal loss accompanied with LB-like structures compri...

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Brain Injection of α-Synuclein Induces Multiple Proteinopathies, Gliosis, and a Neuronal Injury Marker

Cited by 117 publications

References 79 publications

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

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

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

Induction of de novo α-synuclein fibrillization in a neuronal model for Parkinson’s disease

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