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

Abstract

Aggregation of misfolded proteins or peptides is a common feature of neurodegenerative diseases including Alzheimer’s, Parkinson’s, Huntington’s, prion and other diseases. Recent years have witnessed a growing number of reports of overlap in neuropathological features that were once thought to be unique to only one neurodegenerative disorder. However, the origin for the overlap remains unclear. One possibility is that diseases with mixed brain pathologies might arise from cross-seeding of one amyloidogenic protein by aggregated states of unrelated proteins. In the current study we examined whether prion replication can be induced by cross-seeding by α-synuclein or Aβ peptide. We found that α-synuclein aggregates formed in cultured cells or in vitro display cross-seeding activity and trigger misfolding of the prion protein (PrPC) in serial Protein Misfolding Cyclic Amplification reactions, producing self-replicating PrP states characterized by a short C-terminal proteinase K (PK)-resistant region referred to as PrPres. Non-fibrillar α-synuclein or fibrillar Aβ failed to cross-seed misfolding of PrPC. Remarkably, PrPres triggered by aggregated α-synuclein in vitro propagated in animals and, upon serial transmission, produced PrPSc and clinical prion disease characterized by spongiosis and astrocytic gliosis. The current study demonstrates that aggregated α-synuclein is potent in cross-seeding of prion protein misfolding and aggregation in vitro, producing self-replicating states that can lead to transmissible prion diseases upon serial passaging in wild type animals. In summary, the current work documents direct cross-seeding between unrelated amyloidogenic proteins associated with different neurodegenerative diseases. This study suggests that early interaction between unrelated amyloidogenic proteins might underlie the etiology of mixed neurodegenerative proteinopathies.

Accelerated accumulation of retinal α-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson's disease

“…We show, for the first time, that inoculation of brain homogenate of affected mice into young transgenic mice causes a prominent acceleration of retinal pSer129 accumulation, consistent with a "prion-like" propagation of α-synuclein highlighted in many works (Angot et al 2010;Katorcha et al 2017;Luk et al 2012a;Masuda-Suzukake et al 2013;Mougenot et al 2012;Woerman et al 2017). Mougenot et al report accumulation of diffuse α-synuclein (pSer129) inclusions in brains of TgM83 mice inoculated with brain homogenates from Fig.…”

“…caudo-rostral progression of disease from the lower brainstem, followed by the midbrain, forebrain, and cerebral cortex) and as disease progresses, lesion severity in vulnerable brain regions increases (Braak et al 2003). A growing body of in vitro and in vivo evidence describes the ability of pathological α-synuclein to spread transcellularly and induce aggregation by templating protein misfolding (Angot et al 2010;Katorcha et al 2017;Luk et al 2012a;Luk et al 2012b;Mougenot et al 2012;Woerman et al 2017). An in vivo study shows that seeding with an inoculum derived from the brain of clinically ill mice, results in acceleration of α-synuclein-associated disease and shortening of survival time (Mougenot et al 2012).…”

“…Moreover, an in vitro study demonstrates that misfolded α-synuclein displays a self-replicating, as well as a cross-seeding ability (i.e. aggregated α-synuclein can trigger misfolding of cellular prion protein) (Katorcha et al 2017). Another in-vitro study reports that tau fibrils can induce intracellular tangle-like aggregates, suggesting seeding activity of misfolded tau as a potential mechanism of tau propagation in vivo (Guo and Lee 2011).…”

A role of cellular translation regulation associated with toxic Huntingtin protein

“…Here we find that a translation regulator Orb2 can be one of the candidates which can be sequestered by Htt aggregates and thus can make cells deficient for Orb2 function. The sequestration of Orb2, a prion-like protein, by Htt aggregate resembles the cross-seeding phenomenon seen with other proteins associated with neurodegenerative conditions [14, 15, 17, 27, 46, 56]. Orb2 was previously shown to be a modifier of GGGGCC expansion disease model associated with C9orf72 and Ataxin-3 mediated neurodegeneration in Drosophila [6, 7].…”

Effect of the micro-environment on α-synuclein conversion and implication in seeded conversion assays

“…Lastly, the presence of other proteins may affect the aggregation process. Although homotypic seeding is the preferred form of aggregation, heterotypic cross-seeding of α-synuclein with other natively unfolded proteins (such as tau or PrP C [86,87]) has been reported as well.…”