Unique seeding profiles and prion-like propagation of synucleinopathies are highly dependent on the host in human α-synuclein transgenic mice

Lloyd, Grace M.; Sorrentino, Zachary A.; Quintin, Stephan; Gorion, Kimberly-Marie M.; Bell, Brach M.; Paterno, Giavanna; Long, Brooke; Prokop, Stefan

doi:10.1007/s00401-022-02425-4

Cited by 17 publications

(33 citation statements)

References 90 publications

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“…Similar conclusions have been recently published regarding αsynucleinopathies. The strain of the initial inoculum dictates the phenotype and pathology of seeding and spreading; however, the burden and spread of inclusion pathology throughout the neuraxis are also host-dependent [93].…”

Section: Discussionmentioning

confidence: 99%

Common and Specific Marks of Different Tau Strains Following Intra-Hippocampal Injection of AD, PiD, and GGT Inoculum in hTau Transgenic Mice

Ferrer

Andrés‐Benito

Carmona

et al. 2022

IJMS

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Heterozygous hTau mice were used for the study of tau seeding. These mice express the six human tau isoforms, with a high predominance of 3Rtau over 4Rtau. The following groups were assessed: (i) non-inoculated mice aged 9 months (n = 4); (ii) Alzheimer’s Disease (AD)-inoculated mice (n = 4); (iii) Globular Glial Tauopathy (GGT)-inoculated mice (n = 4); (iv) Pick’s disease (PiD)-inoculated mice (n = 4); (v) control-inoculated mice (n = 4); and (vi) inoculated with vehicle alone (n = 2). AD-inoculated mice showed AT8-immunoreactive neuronal pre-tangles, granular aggregates, and dots in the CA1 region of the hippocampus, dentate gyrus (DG), and hilus, and threads and dots in the ipsilateral corpus callosum. GGT-inoculated mice showed unique or multiple AT8-immunoreactive globular deposits in neurons, occasionally extended to the proximal dendrites. PiD-inoculated mice showed a few loose pre-tangles in the CA1 region, DG, and cerebral cortex near the injection site. Coiled bodies were formed in the corpus callosum in AD-inoculated mice, but GGT-inoculated mice lacked globular glial inclusions. Tau deposits in inoculated mice co-localized active kinases p38-P and SAPK/JNK-P, thus suggesting active phosphorylation of the host tau. Tau deposits were absent in hTau mice inoculated with control homogenates and vehicle alone. Deposits in AD-inoculated hTau mice contained 3Rtau and 4Rtau; those in GGT-inoculated mice were mainly stained with anti-4Rtau antibodies, but a small number of deposits contained 3Rtau. Deposits in PiD-inoculated mice were stained with anti-3Rtau antibodies, but rare neuronal, thread-like, and dot-like deposits showed 4Rtau immunoreactivity. These findings show that tau strains produce different patterns of active neuronal seeding, which also depend on the host tau. Unexpected 3Rtau and 4Rtau deposits after inoculation of homogenates from 4R and 3R tauopathies, respectively, suggests the regulation of exon 10 splicing of the host tau during the process of seeding, thus modulating the plasticity of the cytoskeleton.

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Section: Discussionmentioning

confidence: 99%

Common and Specific Marks of Different Tau Strains Following Intra-Hippocampal Injection of AD, PiD, and GGT Inoculum in hTau Transgenic Mice

Ferrer

Andrés‐Benito

Carmona

et al. 2022

IJMS

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“…10 , A and B ). For transgenic mice expressing human A53T αS, termed TgM83 +/− , we previously reported that CNS PFF-injection resulted in widespread αS inclusion pathology throughout the neuroaxis, with the highest levels occurring in the hippocampus, hypothalamus, periaqueductal gray (PAG), midbrain and medulla ( 28 ). Comparatively, x-114 αS reactive inclusion pathology was present in the CNS of these mice but not extensively abundant in the hippocampus, cortex, amygdala, hypothalamus, thalamus, and spine, while moderately present in the midbrain, PAG, and medulla ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Cellular processing of α-synuclein fibrils results in distinct physiological C-terminal truncations with a major cleavage site at residue Glu 114

Quintin¹,

Lloyd²,

Paterno³

et al. 2023

Journal of Biological Chemistry

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“…This pathological spreading was contingent upon the presence of endogenous α-synuclein, since no α-synuclein-containing aggregates were observed when inoculations were made in α-synuclein null (Snca −/− ) mice [13,14]. Distinct histopathological and behavioral phenotypes were described as a result of injections of α-synuclein fibrils with different structural characteristics (so called α-synuclein "strains"), possibly mimicking the heterogeneous pathology that characterizes different human synucleinopathies [19][20][21]. Taken together, these observations strongly supported an intriguing mechanism of neuron-to-neuron transfer of α-synuclein lesions.…”

Section: Introductionmentioning

confidence: 99%

Overexpression-Induced α-Synuclein Brain Spreading

et al. 2023

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Interneuronal transfer of pathological α-synuclein species is thought to play an important role in the progressive advancement of Lewy pathology and increasing severity of clinical manifestations in Parkinson’s and other diseases commonly referred to as synucleinopathies. Pathophysiological conditions and mechanisms triggering this trans-synaptic spreading bear therefore significant pathogenetic implications but have yet to be fully elucidated. In vivo experimental models support the conclusion that increased expression of intraneuronal α-synuclein can itself induce protein spreading throughout the brain as well as from the brain to peripheral tissues. For example, overexpression of α-synuclein targeted to the rodent dorsal medulla oblongata results in its transfer and accumulation into recipient axons innervating this brain region; through these axons, α-synuclein can then travel caudo-rostrally and reach other brain sites in the pons, midbrain, and forebrain. When protein overexpression is induced in the rodent midbrain, long-distance α-synuclein spreading can be followed over time; spreading-induced α-synuclein accumulation affects lower brain regions, including the dorsal motor nucleus of the vagus, proceeds through efferent axons of the vagus nerve, and is ultimately detected within vagal motor nerve endings in the gastric wall. As discussed in this review, animal models featuring α-synuclein overexpression not only support a relationship between α-synuclein burden and protein spreading but have also provided important clues on conditions/mechanisms capable of promoting interneuronal α-synuclein transfer. Intriguing findings include the relationship between neuronal activity and protein spreading and the role of oxidant stress in trans-synaptic α-synuclein mobility.

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Unique seeding profiles and prion-like propagation of synucleinopathies are highly dependent on the host in human α-synuclein transgenic mice

Cited by 17 publications

References 90 publications

Common and Specific Marks of Different Tau Strains Following Intra-Hippocampal Injection of AD, PiD, and GGT Inoculum in hTau Transgenic Mice

Common and Specific Marks of Different Tau Strains Following Intra-Hippocampal Injection of AD, PiD, and GGT Inoculum in hTau Transgenic Mice

Cellular processing of α-synuclein fibrils results in distinct physiological C-terminal truncations with a major cleavage site at residue Glu 114

Overexpression-Induced α-Synuclein Brain Spreading

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