Conformational templating of α-synuclein aggregates in neuronal-glial cultures

Sacino, Amanda N.; Thomas, M. Albert; Ceballos‐Diaz, Carolina; Cruz, Pedro; Rosario, Awilda M.; Lewis, Jada; Giasson, Benoit I.; Golde, Todd E.

doi:10.1186/1750-1326-8-17

Cited by 64 publications

(80 citation statements)

References 59 publications

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“…Previous experimental studies have provided evidence for in vivo prion-like spread of αS pathology (21-26); however, several findings here, and in other recent studies from our group, suggest that additional nonexclusive mechanisms inducing or promoting αS inclusion pathology formation should be considered (33,(51)(52)(53). Indeed, (i) the distribution of αS pathology in M83 Tg mice IM injected with various forms of αS was identical to that seen in untreated, aged M83 Tg mice, (ii) IM injection of a nonamyloidogenic form of αS (Δ71-82) induced CNS αS inclusion pathology, albeit less efficiently than fibrillar αS, and (iii) there were significant increases of both astrogliosis and microgliosis associated with the regions where abundant αS pathology was induced.…”

Section: Discussionmentioning

confidence: 44%

“…Under experimental native and physiological conditions, Δ71-82 αS is refractory to amyloid formation, and it does not promote or influence amyloid formation of full-length αS (32,33,36,37); however, under nonphysiological conditions (i.e., the presence of SDS), it can be artificially induced to form amyloid fibrils (54). At present, we cannot completely exclude the possibility that a small amount of soluble Δ71-82 αS may spontaneously form amyloid seeds in vivo.…”

Section: Discussionmentioning

confidence: 91%

“…The N-terminal truncated 21-140 αS hfib21-140 protein was used because it enables assessment of aggregation by endogenous αS by detection with N-terminal-specific αS antibodies (32)(33)(34)(35). Nonamyloidogenic human Δ71-82 αS has a deletion of αS required for amyloid formation and lacks the ability to form or seed αS amyloid in vitro and in cultured cells under relatively physiologic conditions (32,33,36,37). IM injection of human Δ71-82 αS was used to test the hypothesis that induction of αS pathology occurs through amyloidogenic conformational templating.…”

Section: Resultsmentioning

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.

289

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: 44%

Section: Discussionmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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.

289

343

View full text Add to dashboard Cite

show abstract

“…According to previous reports, we found that neurons exposed to aSyn aggregates develop S129 p-aSyn inclusions, displaying increased levels of insoluble aSyn (38,49). However, in contrast to other studies (39), overexpression of the cellular aSyn or expression of the human form was not required. The inclusions formed could be classified depending on their localization in the cell.…”

Section: Discussionmentioning

confidence: 47%

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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“…In neurons, astrocytes and mixed primary cells, sonicated A53T fibrils seeded 'flame-like inclusions', whereas small E46K fibrils prompted the formation of punctate roundshaped structures depending on the form of α-syn expressed. In addition, the inclusions could be transferred during passaging in a prion-like manner [19]. Further evidence for the prion-like seeding mechanism of α-syn has arisen from a variety of in vivo experimentation at the cellular, intercellular and tissue levels which has been strengthened by sporadic cases of transmission in mesencephalic transplants of PD patients.…”

Section: Introductionmentioning

confidence: 99%

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Illes‐Toth

Ramos

Cappai

et al. 2015

Biochemical Journal

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Misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies is associated with a range of neurological disorders, including Parkinson's disease (PD). The cell-to-cell transmission of α-syn pathology has been linked to soluble amyloid oligomer populations that precede Lewy body formation. Oligomers produced in vitro under certain conditions have been demonstrated to induce intracellular aggregation in cell culture models. In the present study, we characterize, by ESI-ion mobility spectrometry (IMS)-MS, a specific population of α-syn oligomers. These MS-compatible oligomers were compared with oligomers with known seeding and pore-forming capabilities and were shown to have the ability to induce intracellular aggregation. Each oligomer type was shown to have distinct epitope profiles that correlated with their toxic gain-of-function. Structurally, the MS compatible oligomers populated a range of species from dimers through to hexamers. Lower-order oligomers were structurally diverse and consistent with unstructured assemblies. Higher-order oligomers were shown to be compact with ring-like structures. The observation of this compact state may explain how this natively disordered protein is able to transfer pathology from cell to cell and avoid degradation by cellular proteases.

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Conformational templating of α-synuclein aggregates in neuronal-glial cultures

Cited by 64 publications

References 59 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

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

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

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