Transmission of multiple system atrophy prions to transgenic mice

Abstract

Prions are proteins that adopt alternative conformations, which become self-propagating. Increasing evidence argues that prions feature in the synucleinopathies that include Parkinson's disease, Lewy body dementia, and multiple system atrophy (MSA). Although TgM83 +/+ mice homozygous for a mutant A53T α-synuclein transgene begin developing CNS dysfunction spontaneously at ∼10 mo of age, uninoculated TgM83 +/− mice (hemizygous for the transgene) remain healthy. To determine whether MSA brains contain α-synuclein prions, we inoculated the TgM83 +/− mice with brain homogenates from two pathologically confirmed MSA cases. Inoculated TgM83 +/− mice developed progressive signs of neurologic disease with an incubation period of ∼100 d, whereas the same mice inoculated with brain homogenates from spontaneously ill TgM83 +/+ mice developed neurologic dysfunction in ∼210 d. Brains of MSA-inoculated mice exhibited prominent astrocytic gliosis and microglial activation as well as widespread deposits of phosphorylated α-synuclein that were proteinase K sensitive, detergent insoluble, and formic acid extractable. Our results provide compelling evidence that α-synuclein aggregates formed in the brains of MSA patients are transmissible and, as such, are prions. The MSA prion represents a unique human pathogen that is lethal upon transmission to Tg mice and as such, is reminiscent of the prion causing kuru, which was transmitted to chimpanzees nearly 5 decades ago.neurodegeneration | bioluminescence imaging | seeding | proteinopathies

Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice

“…In both cases, αS pathology is associated with a rapidly progressive motor phenotype that is subtly distinct from that in untreated, aged M83 Tg mice due to the initial foot drop presentation and the heightened neuroinflammatory response. From our findings, IM injections appear to induce a more rapid lethal motor phenotype (50-120 d incubation time) than reported in some studies where either homozygous or hemizygous M83 Tg were intracerebrally inoculated with CNS extracts from symptomatic M83 Tg (∼200 d incubation time) (23,24). However, Luk et al (21) reported that, in similar M83 Tg CNS extract transmission studies or with intracerebral injection of recombinant fib αS in homozygous M83 Tg mice, the incubation time to cause motor impairments was closer to what we observed resulting from IM injection of fib αS (i.e., ∼100 d) (21).…”

“…Our ability to now synchronously and rapidly induce a motor phenotype and αS pathology by a peripheral injection of αS may prove invaluable in future studies exploring mechanisms of pathology induction and αS toxicity and may extend recent studies showing rapid induction following intracerebral inoculation (21)(22)(23)(24)(25)(26). Our finding that disease onset in M83 Tg mice can be shortened, predicted, and synchronized through a simple manipulation provides a valuable model to accelerate studies designed to fully understand the mechanisms underlying induction of the inclusion pathology and motor phenotype, but also to enable much more rapid and cost-effective preclinical testing of novel PD therapies.…”

“…And it has been suggested that αS pathology might originate in the nerves of the PNS and spread to the CNS (14). Experimentally, it has been reported that intracerebral injections of preformed amyloidogenic αS fibrils in nontransgenic (nTg) and αS transgenic (Tg) mice induce the formation of intracellular αS inclusions that appear to progress from the site of injection (21)(22)(23)(24)(25)(26). Collectively, these studies support the notion that αS inclusion pathology may propagate via a prion-like conformational self-templating mechanism (27,28).…”

Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping

“…4 A and B). This coexistence distinguishes the hSOD1 D90A mice from previous disease models where the variation of strains is typically observed between individuals (1,34,35,41). Even so, the hSOD1 D90A mice highlight the notion that strain variation influences pathology, as previously observed for prions (27,28), and in patients and models for synucleopathies (33), Alzheimer's disease (1,35,36), and tauopathies (34).…”

Protein Quality Control in Health and Disease

“…These observations suggest that LBs serve as quality-control compartments that enable efficient digestion of toxic a-synuclein assemblies. Recent studies show that a-synuclein prionlike assemblies cause multiple system atrophy, which shares many features observed in PD (Watts et al 2013;Prusiner et al 2015).…”