The clinical and pathological differences between synucleinopathies such as Parkinson's disease and multiple system atrophy have been postulated to stem from unique strains of α-synuclein aggregates, akin to what occurs in prion diseases. Here, we demonstrate that inoculation of transgenic mice with different strains of recombinant or brain-derived α-synuclein aggregates produces clinically and pathologically distinct diseases. Strain-specific differences were observed in the signs of neurological illness, time to disease onset, morphology of cerebral α-synuclein deposits, and the conformational properties of the induced aggregates. Moreover, different strains targeted distinct cellular populations and cell types within the brain, recapitulating the selective targeting observed between human synucleinopathies. Strain-specific clinical, pathological, and biochemical differences were faithfully maintained upon serial passaging, implying that αsynuclein propagates via prion-like conformational templating. Thus, pathogenic α-synuclein exhibits key hallmarks of prion strains, providing evidence that disease heterogeneity among the synucleinopathies is caused by distinct α-synuclein strains.Parkinson's disease (PD) and related diseases, including dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), are progressive neurodegenerative disorders. The brains of PD, DLB, and MSA patients contain intracellular inclusions composed of aggregated α-synuclein (α-syn). Thus, these diseases are commonly referred to as αsynucleinopathies, or simply synucleinopathies 1 . α-Syn is a 140-amino acid cytoplasmic protein that is found within presynaptic nerve terminals and is involved in the assembly of SNARE complexes 2 . In disease, α-syn polymerizes into insoluble β-sheet-rich protein aggregates that become phosphorylated at residue Ser129 and deposit within the central nervous system 3,4 . α-Syn is believed to play a central pathogenic role in the synucleinopathies since mutation of the gene encoding α-syn causes early-onset PD 5 .There is mounting evidence that α-syn becomes "prion-like" during disease, leading to a progressive cell-to-cell spreading of protein aggregates within the brain 6 . Prions are selfpropagating protein aggregates that cause neurodegenerative disorders such as Creutzfeldt-Jakob disease in humans and scrapie in sheep. Prion replication and spreading is thought to occur via a template-directed refolding mechanism, in which aggregated prion protein (PrP) catalyzes the conformational conversion of properly-folded PrP into additional copies of the misfolded form 7 . Similar to the experimental transmission of prion disease, injection of mice with pre-formed α-syn aggregates induces the aggregation and deposition of α-syn within the brain and, in some instances, accelerates the onset of neurological illness [8][9][10][11][12][13] . The prionlike behavior of α-syn aggregates provides a potential molecular explanation for the progressive nature of PD and related synucleinopathies.The synucleinopathies ar...

Several ruminal cellulolytic bacteria species are sensitive to pH and could therefore be used as biomarkers to determine the risk of sub-acute ruminal acidosis (SARA) in finishing lambs. This study compared a 2–4 h post feeding ruminal pH measurement to abundances of the ruminal pH-sensitive bacteria to evaluate the risk of SARA in a herd of 120 finishing lambs. The lambs were reared in individual units for 50 days. Ruminal fluid was collected by use of an orogastric tube on day 51 2-4 h after feeding. Although the lambs were fed an identical diet, they responded differently in the abundances of four ruminal pH sensitive cellulolytic bacteria (Ruminococcus albus, Ruminococcus flavefaciens and Fibrobacter succinogenes and Butyrivibrio fibrisolvens). Lambs with the most or the least cellulolytic bacteria were then classified as either lower SARA risk (LSR, n = 10) or higher SARA risk group (HSR, n = 10), respectively. Data showed that the ruminal pH and VFA profiles were uncorrelated with the number of cellulolytic bacteria (P > 0.050). Lambs with the HSR showed lower ruminal pH (P = 0.013) and acetate to propionate ratio (P = 0.018), higher concentrations of lactate (P = 0.035) and proportion of propionate (P = 0.033) compared to those with the LSR. The DMI and ADG did not differ in LSR and HSR lambs (P > 0.050). A diversity analysis revealed significantly lower diversity in HSR lambs than in LSR (Simpson index, P = 0.004). The relative abundances of the phyla Bacteroidetes, Fibrobacteres, Verruomicrobia, and Proteobacteria were higher in LSR lambs than in HSR (P < 0.050). The abundances of several phyla including Firmicutes, Tenericutes and Actinobacteria were higher in the HSR than in the LSR group (P < 0.050). The bacterial communities of the LSR and HSR clustered separately in rumen based on the Unifrac distances, indicating distinct bacteria communities at OTU level between the LSR and HSR lambs. Overall, there was no correlation between 2 and 4 h post-feeding ruminal pH and the abundance of pH-sensitive bacteria and the amount of these bacteria could be used as a potential biomarker of SARA in lamb herd.

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The amyloid cascade hypothesis posits that the initiating event in Alzheimer’s disease (AD) is the aggregation and deposition of the β-amyloid (Aβ) peptide, which is a proteolytic cleavage product of the amyloid precursor protein (APP). Mounting evidence suggests that the formation and spread of prion-like Aβ aggregates during AD may contribute to disease progression. Inoculation of transgenic mice that overexpress APP with pre-formed Aβ aggregates results in the prion-like induction of cerebral Aβ deposition. To determine whether Aβ deposition can also be induced when physiological APP levels are present in the brain, we inoculated AppNL-F mice, a knock-in model of AD that avoids potential artifacts associated with APP overexpression, with Aβ aggregates derived from the brains of AD patients or transgenic mice. In all cases, induced Aβ deposition was apparent in the corpus callosum, olfactory bulb, and meningeal blood vessels of inoculated mice at 130–150 days post-inoculation, whereas uninoculated and buffer-inoculated animals exhibited minimal or no Aβ deposits at these ages. Interestingly, despite being predominantly composed of protease-resistant Aβ42 aggregates, the induced parenchymal Aβ deposits were largely diffuse and were unreactive to an amyloid-binding dye. These results demonstrate that APP overexpression is not a prerequisite for the prion-like induction of cerebral Aβ deposition. Accordingly, spreading of Aβ deposition may contribute to disease progression in AD patients.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0529-x) contains supplementary material, which is available to authorized users.