Prion infection promotes extensive accumulation of α-synuclein in aged human α-synuclein transgenic mice

Abstract

In neurodegenerative disorders of the aging population, misfolded proteins, such as PrP(Sc), α-synuclein, amyloid β protein and tau, can interact resulting in enhanced aggregation, cross seeding and accelerated disease progression. Previous reports have shown that in Creutzfeldt-Jakob disease and scrapie, α-synuclein accumulates near PrP(Sc) deposits. However, it is unclear if pre-existing human α-synuclein aggregates modified prion disease pathogenesis, or if PrP(Sc) exacerbates the α-synuclein pathology. Here, we inoculated infectious prions into aged α-synuclein transgenic (tg) and non-transgenic littermate control mice by the intracerebral route. Remarkably, inoculation of RML and mNS prions into α-synuclein tg mice resulted in more extensive and abundant intraneuronal and synaptic α-synuclein accumulation. In addition, infectious prions led to the formation of perineuronal α-synuclein deposits with a neuritic plaque-like appearance. Prion pathology was unmodified by the presence of α-synuclein. However, with the mNS prion strain there was a modest but significant acceleration in the time to terminal prion disease in mice having α-synuclein aggregates as compared with non-tg mice. Taken together, these studies support the notion that PrP(Sc) directly or indirectly promotes α-synuclein pathology.

Cross-seeding of prions by aggregated α-synuclein leads to transmissible spongiform encephalopathy

“…Consistent with this hypothesis is a study in which shorter incubation times to prion disease were observed in transgenic mice that overexpress human A53T α-synuclein compared to non-transgenic controls inoculated with three prion strains [ 18 ]. Another study reported that inoculation of prions into aged transgenic mice overexpressing human wild type α-synuclein resulted in more extensive and abundant intraneuronal and synaptic accumulation of α-synuclein relative to non-transgenic control mice [ 19 ]. In addition, in agreement with the latter mechanism is the observation that CJD patients exhibit impairments of the nigrostriatal pathway, which is a hallmark of Parkinson’s disease [ 7 ].…”

Crosstalk Between Alpha-Synuclein and Other Human and Non-Human Amyloidogenic Proteins: Consequences for Amyloid Formation in Parkinson’s Disease

“…There are many more putative cross-reactivity reactions between aS and human amyloidogenic proteins that await to be mechanistically assessed in vitro. For example, expression of a mutant SOD1 (amyloidogenic protein in ALS) in cells promoted cellular aS aggregation [84] and inoculation of infectious prions into aS-expressing transgenic mice promoted extensive aS aggregate deposits and exacerbated aS pathology [85]. These studies hint to possible cross-reactivity on the molecular level such that, in both cases, interaction with the other protein (as monomer or amyloid) would accelerate aS aggregation.…”

Review: Novel treatment strategies targeting alpha‐synuclein in multiple system atrophy as a model of synucleinopathy

“…Moreover, increased α‐syn aggregation may lead to defective protein clearance and autophagy deficits and, therefore, to increased release of α‐syn to the extracellular environment and consequent spreading. The prion‐like characteristics of α‐syn aggregates may also lead to abnormal α‐syn conformational changes and trigger its accumulation in acceptor cells . Therefore, it follows that α‐syn‐centric therapies should target one or more of these dysregulated mechanisms to effectively reduce α‐syn pathology.…”