Multiple system atrophy prions transmit neurological disease to mice expressing wild-type human α-synuclein

Holec, Sara A. M.; Lee, Sang Hoon; Oehler, Abby; Ooi, Felicia K.; Mordes, Daniel A.; Olson, Steven H.; Prusiner, Stanley B.; Woerman, Amanda L.

doi:10.1007/s00401-022-02476-7

Cited by 19 publications

(13 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In these experiments, we used the TgM20 +/- mouse model that uses the Prnp promoter to express WT human α-synuclein [ 17 ], making this the best model available to test this effect. We recently showed that both WT PFFs and MSA patient samples propagate with high fidelity in TgM20 +/- mice, inducing neurological disease over an extended incubation period compared to transmission studies in the TgM83 +/- mouse model [ 46 ]. Here, eight-week-old TgM20 +/- mice inoculated with 30 μL of 1% brain homogenate from control patient samples or 30 μg E46K PFFs were assessed biweekly for the onset of neurological signs.…”

Section: Resultsmentioning

confidence: 99%

“…(A) Kaplan-Meier plot shows five of eight mice inoculated with E46K PFFs developed neurological disease by 475 days postinoculation (dpi; P > 0.05). Incubation times for control-inoculated mice previously reported in Holec, et al ., 2022 [ 46 ]. (B) Two brain homogenates from TgM20 +/- mice inoculated with control patient samples and three homogenates from mice inoculated with E46K PFFs were assayed for the presence of insoluble α-synuclein following detergent extraction (EP1536Y primary antibody).…”

Section: Resultsmentioning

confidence: 99%

“… a Colors represent heat map of infectivity with blue indicating high infectivity for a given cell line and red indicating low infectivity for a given cell line. Cell infection data from mice inoculated with samples C9 and C17 reported in Holec, et al, 2022 [ 46 ]. **** = P < 0.0001 compared to control-patient samples C9 and C17.…”

Section: Resultsmentioning

confidence: 99%

“…(A) Quantification of stained brain slices showed no significant phosphorylated α-synuclein inclusions were present in the caudate (Cd), hippocampus (HC), piriform cortex and amygdala (Pir), thalamus (Thal), hypothalamus (HTH), midbrain (Mid), or pons ( P > 0.05). Neuropathology data for control-inoculated mice was previously reported in Holec, et al ., 2022 [ 46 ]. (B) Representative images of the HC, amygdala, and pons from mice inoculated with either control patient sample C17 (top) or E46K PFFs (bottom).…”

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

The E46K mutation modulates α-synuclein prion replication in transgenic mice

et al. 2022

Self Cite

View full text Add to dashboard Cite

In multiple system atrophy (MSA), the α-synuclein protein misfolds into a self-templating prion conformation that spreads throughout the brain, leading to progressive neurodegeneration. While the E46K mutation in α-synuclein causes familial Parkinson’s disease (PD), we previously discovered that this mutation blocks in vitro propagation of MSA prions. Recent studies by others indicate that α-synuclein adopts a misfolded conformation in MSA in which a Greek key motif is stabilized by an intramolecular salt bridge between residues E46 and K80. Hypothesizing that the E46K mutation impedes salt bridge formation and, therefore, exerts a selective pressure that can modulate α-synuclein strain propagation, we asked whether three distinct α-synuclein prion strains could propagate in TgM47+/- mice, which express human α-synuclein with the E46K mutation. Following intracranial injection of these strains, TgM47+/- mice were resistant to MSA prion transmission, whereas recombinant E46K preformed fibrils (PFFs) transmitted neurological disease to mice and induced the formation of phosphorylated α-synuclein neuropathology. In contrast, heterotypic seeding following wild-type (WT) PFF–inoculation resulted in preclinical α-synuclein prion propagation. Moreover, when we inoculated TgM20+/- mice, which express WT human α-synuclein, with E46K PFFs, we observed delayed transmission kinetics with an incomplete attack rate. These findings suggest that the E46K mutation constrains the number of α-synuclein prion conformations that can propagate in TgM47+/- mice, expanding our understanding of the selective pressures that impact α-synuclein prion replication.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

The E46K mutation modulates α-synuclein prion replication in transgenic mice

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…If seeding assays can be more widely developed and applied in neurodegenerative diseases, as seems likely, these findings might provoke exploration of long presymptomatic seeding phases in other disorders. Discoveries in recent years have revealed fundamental aspects of common neurodegenerative diseases similar to prion diseases, particularly in proteopathic seed propagation, transmissibility and strain biology (52)(53)(54)(55)(56). The RT-QuIC-type proteopathic seed amplification assay borne out of the prion disease field has the potential to extend the presymptomatic stage earlier than the neurodegenerative phase, which is already very well characterised by imaging, neuropsychometric, fluid markers, etc.…”

Section: Discussionmentioning

confidence: 99%

Trajectories of neurodegeneration and seed amplification biomarkers prior to disease onset in individuals at risk of prion disease

Mok

Nihat

Majbour

et al. 2022

Preprint

View full text Add to dashboard Cite

Human prion diseases are remarkable for long incubation times followed by typically rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at-risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC), and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied a total of 648 CSF and plasma samples, including importantly, 16 people who had samples taken when healthy but later developed IPD (converters, range from 9.9 prior to, and 7.4 years after onset). A second generation (IQ-CSF) RT-QuIC assay was used to screen symptomatic IPD samples, followed by optimisation for other IPDs, before the entire collection of at-risk samples was screened using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) levels were measured in plasma and CSF. IQ-CSF RT-QuIC proved 100% sensitive and specific for sporadic CJD, iCJD and familial CJD phenotypes, and subsequently detected seeding activity in four CSF samples from three PRNP E200K carriers in the presymptomatic phase, one of whom converted shortly after but the other two remain asymptomatic after two and three years of follow up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease and was positive in a CSF sample from an individual at risk of P102L IPD. No compatible RT-QuIC assay iterations were discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in slowly progressive forms of IPDs, with highly statistically significant differences in mean values segregating normal control (together with IPD > 2 years to onset) from IPD < 2 years to onset and symptomatic IPD cohorts. The trajectories of biomarker change appeared to correspond to expected fast and slow clinical phenotypes of progression in IPD with plasma GFAP changes preceding NfL changes. We propose a staging system for prion diseases based on the presence of clinical, seeding and neurodegeneration features.

show abstract

α-Synuclein Conformational Strains as Drivers of Phenotypic Heterogeneity in Neurodegenerative Diseases

Watts

2023

Journal of Molecular Biology

View full text Add to dashboard Cite

Multiple system atrophy prions transmit neurological disease to mice expressing wild-type human α-synuclein

Cited by 19 publications

References 40 publications

The E46K mutation modulates α-synuclein prion replication in transgenic mice

The E46K mutation modulates α-synuclein prion replication in transgenic mice

Trajectories of neurodegeneration and seed amplification biomarkers prior to disease onset in individuals at risk of prion disease

α-Synuclein Conformational Strains as Drivers of Phenotypic Heterogeneity in Neurodegenerative Diseases

Contact Info

Product

Resources

About