Neuroinvasion of α-Synuclein Prionoids after Intraperitoneal and Intraglossal Inoculation

Breid, Sara; Bernis, María Eugenia; Babila, Julius T.; Garza, María Carmen; Wille, Holger; Tamgüney, Gültekin

doi:10.1128/jvi.01399-16

Cited by 89 publications

(84 citation statements)

References 54 publications

(58 reference statements)

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“…; Breid et al . ). The hypothesis of the present study is that M83 disease can be accelerated by the intraperitoneal inoculation of sick M83 brain homogenates and that the accumulation of α‐syn P in the central nervous system may depend on the initial level of expression of the normal α‐syn protein in the mouse brain.…”

mentioning

confidence: 97%

‘Prion‐like’ propagation of the synucleinopathy of M83 transgenic mice depends on the mouse genotype and type of inoculum

Sargent

Verchère

Lazizzera

et al. 2017

Journal of Neurochemistry

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The M83 transgenic mouse is a model of human synucleinopathies that develops severe motor impairment correlated with accumulation of the pathological Ser129-phosphorylated α-synuclein (α-syn ) in the brain and spinal cord. M83 disease can be accelerated by intracerebral inoculation of brain extracts from sick M83 mice. This has also recently been described using peripheral routes, injecting recombinant preformed α-syn fibrils into the muscle or the peritoneum. Here, we inoculated homozygous and/or hemizygous M83 neonates via the intraperitoneal and/or intracerebral routes with two different brain extracts: one from sick M83 mice inoculated with brain extract from other sick M83 mice, and the other derived from a human multiple system atrophy source passaged in M83 mice. Detection of α-syn using ELISA and western blot confirmed the disease in mice. The distribution of α-syn in the central nervous system was similar, independently of the inoculum or inoculation route, consistent with previous studies describing M83 disease. ELISA tests revealed higher levels of α-syn in homozygous than in hemizygous sick M83 mice, at least after IC inoculation. Interestingly, the immunoreactivity of α-syn detected by ELISA was significantly lower in M83 mice inoculated with the multiple system atrophy inoculum than in M83 mice inoculated with the M83 inoculum, at the first two passages. 'Prion-like' propagation of the synucleinopathy up to the clinical disease was accelerated by both intracerebral and intraperitoneal inoculations of brain extracts from sick mice. This acceleration, however, depends on the levels of α-syn expression by the mouse and the type of inoculum.

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mentioning

confidence: 97%

‘Prion‐like’ propagation of the synucleinopathy of M83 transgenic mice depends on the mouse genotype and type of inoculum

Sargent

Verchère

Lazizzera

et al. 2017

Journal of Neurochemistry

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“…Our findings support a recent study which also demonstrated the ability for ␣S fibrils, i.p. injected in transgenic mice expressing the A53T ␣S protein, to induce ␣S pathology and paralysis (50). Although the latter study provides insight into the potential efficiency of this peripheral route, we provide a higher powered study and include a number of control proteins which aim to better understand the component responsible for ␣S pathology and disease induction.…”

Section: Discussionmentioning

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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“…Although it remains to be supported, a role for microglia and other immune cells in such periphery-to-CNS propagation of aggregated α-syn cannot be discounted. Indeed, the transmission of α-syn from the periphery into the brain is often accompanied by increased microglial activity and neuroinflammation (Breid et al 2016). To sum up, circulating glial cells may play various roles in the spread of excess aggregated α-syn, either over short or long distances.…”

Section: Do Non-neuronal Cells Play a Role In Neuron To Neuron Transmmentioning

confidence: 99%

The concept of alpha-synuclein as a prion-like protein: ten years after

2018

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Parkinson's disease is characterized by the loss of nigrostriatal dopaminergic signaling and the presence of alpha-synuclein aggregates (also called Lewy bodies and neurites) throughout the brain. In 2003, Braak and colleagues created a staging system for Parkinson's disease describing the connection between the alpha-synuclein pathology and disease severity. Later, they suggested that the pathology might initially be triggered by exogenous insults targeting the gut and olfactory system. In 2008, we and other groups documented Lewy pathology in grafted neurons in people with Parkinson's disease who had been transplanted over a decade prior to autopsy. We proposed that the Lewy pathology in the grafted neurons was the result of permissive templating or prion-like spread of alpha-synuclein pathology from neurons in the host to those in the grafts. During the following ten years, several studies described the transmission of alpha-synuclein pathology between neurons, both in cell culture and in experimental animals. Recent research has also begun to identify underlying molecular mechanisms. Collectively, these experimental studies tentatively support the idea that the progression from one Braak stage to the next is the consequence of prion-like propagation of Lewy pathology. However, definitive proof that intercellular propagation of alpha-synuclein pathology occurs in Parkinson's disease cases has proven difficult to secure. In this review, we highlight several open questions that currently prevent us from concluding with certainty that prion-like transfer of alpha-synuclein contributes to the progression of Parkinson's disease.

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Neuroinvasion of α-Synuclein Prionoids after Intraperitoneal and Intraglossal Inoculation

Cited by 89 publications

References 54 publications

‘Prion‐like’ propagation of the synucleinopathy of M83 transgenic mice depends on the mouse genotype and type of inoculum

‘Prion‐like’ propagation of the synucleinopathy of M83 transgenic mice depends on the mouse genotype and type of inoculum

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

The concept of alpha-synuclein as a prion-like protein: ten years after

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