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Prion diseases uniquely manifest in three distinct forms: inherited, sporadic, and infectious. Wild-type prions are responsible for the sporadic and infectious versions, while mutant prions cause inherited variants like fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). Although some drugs can prolong prion incubation times up to four-fold in rodent models of infectious prion diseases, no effective treatments for FFI and fCJD have been found. In this study, we evaluated the efficacy of various anti-prion drugs on newly-developed knock-in mouse models for FFI and fCJD. These models express bank vole prion protein (PrP) with the pathogenic D178N and E200K mutations. We applied various drug regimens known to be highly effective against wild-type prions in vivo as well as a brain-penetrant compound that inhibits mutant PrPSc propagation in vitro. None of the regimens tested (Anle138b, IND24, Anle138b + IND24, cellulose ether, and PSCMA) significantly extended disease-free survival or prevented mutant PrPSc accumulation in either knock-in mouse model, despite their ability to induce strain adaptation of mutant prions. Our results show that anti-prion drugs originally developed to treat infectious prion diseases do not necessarily work for inherited prion diseases, and that the recombinant sPMCA is not a reliable platform for identifying compounds that target mutant prions. This work underscores the need to develop therapies and validate screening assays specifically for mutant prions, as well as anti-prion strategies that are not strain-dependent. We treated two mouse models of inherited prion disease with a variety of drug treatments, including several which have been previously shown to be highly effective against infectious prion diseases and another that biochemically inhibits the formation of mutant prion proteins in a test tube assay. Surprisingly none of the treatments improved lifespans in the either mouse model even though several treat, Funding Agencies|National Institute for Neurological Diseases and Stroke [R37NS125431, R01NS117276, R01NS118796]; National Institutes of Health [P20-GM113132]

Unique strains of a-synuclein aggregates have been postulated to underlie the spectrum of clinical and pathological presentations seen across the synucleinopathies. Whereas multiple system atrophy (MSA) is associated with a predominance of oligodendroglial a-synuclein inclusions, a-synuclein aggregates in Parkinson's disease (PD) preferentially accumulate in neurons. The G51D mutation in the SNCA gene encoding a-synuclein causes an aggressive, early-onset form of PD that exhibits clinical and neuropathological traits reminiscent of both PD and MSA. To assess the strain characteristics of G51D PD a-synuclein aggregates, we performed propagation studies in M83 transgenic mice by intracerebrally inoculating patient brain extracts. The properties of the induced a-synuclein aggregates in the brains of injected mice were examined using immunohistochemistry, a conformational stability assay, and by performing a-synuclein seed amplification assays. Unlike MSA-injected mice, which developed a progressive motor phenotype, G51D PD-inoculated animals remained free of overt neurological illness for up to 18 months post-inoculation. However, a subclinical synucleinopathy was present in G51D PD-inoculated mice, characterized by the accumulation of a-synuclein aggregates in restricted regions of the brain. The induced a-synuclein aggregates in G51D PD-injected mice exhibited distinct properties in a seed amplification assay and were much more stable than those present in mice injected with MSA extract, which mirrored the differences observed between human MSA and G51D PD brain samples. These results suggest that the G51D SNCA mutation specifies the formation of a slowly propagating a-synuclein strain that more closely resembles a-synuclein aggregates associated with PD than MSA.

When injected into genetically modified mice, aggregates of the amyloid-beta (A beta) peptide from the brains of Alzheimers disease (AD) patients or transgenic AD mouse models seed cerebral A beta deposition in a prion-like fashion. Within the brain, A beta exists as a pool of distinct C-terminal variants with lengths ranging from 37 to 43 amino acids, yet the relative contribution of individual C-terminal A beta variants to the seeding behavior of A beta aggregates remains unknown. Here, we have investigated the relative seeding activities of A beta aggregates composed exclusively of recombinant A beta 38, A beta 40, A beta 42, or A beta 43. Cerebral A beta 42 levels were not increased in App(NL-F) knock-in mice injected with A beta 38 or A beta 40 aggregates and were only increased in a subset of mice injected with A beta 42 aggregates. In contrast, significant accumulation of A beta 42 was observed in the brains of all mice inoculated with A beta 43 aggregates, and the extent of A beta 42 induction was comparable to that in mice injected with brain-derived A beta seeds. Mice inoculated with A beta 43 aggregates exhibited a distinct pattern of cerebral A beta pathology compared to mice injected with brain-derived A beta aggregates, suggesting that recombinant A beta 43 may polymerize into a unique strain. Our results indicate that aggregates containing longer A beta C-terminal variants are more potent inducers of cerebral A beta deposition and highlight the potential role of A beta 43 seeds as a crucial factor in the initial stages of A beta pathology in AD., Funding Agencies|Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR) [MOP-136899, PJT-173497]; Alzheimer Society Canada/Brain Canada [16-13]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2016-00748]

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 alpha-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 alpha-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 alpha-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 among human synucleinopathies. Strain-specific clinical, pathological and biochemical differences were faithfully maintained after serial passaging, which implies that alpha-synuclein propagates via prion-like conformational templating. Thus, pathogenic alpha-synuclein exhibits key hallmarks of prion strains, which provides evidence that disease heterogeneity among the synucleinopathies is caused by distinct alpha-synuclein strains.