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.
Highlights
Aggregation of misfolded proteins or peptides is a common feature of neurodegenerative diseases including Alzheimer’s, Parkinson’s, Huntington’s, prion and other diseases [1,2]
One possibility is that disease that have mixed brain pathologies might arise from cross-seeding of one amyloidogenic protein by fibrillar states of unrelated proteins
The current study examined whether prion replication can be induced by cross-seeding by α-synuclein or Aβ peptide in their aggregated states
Summary
Aggregation of misfolded proteins or peptides is a common feature of neurodegenerative diseases including Alzheimer’s, Parkinson’s, Huntington’s, prion and other diseases [1,2]. Each neurodegenerative disease is characterized by aggregation of one or two disease-specific proteins or peptides, for instance, Aβ and tau in Alzheimer’s disease, α-synuclein in Parkinson’s disease, or prion protein in prion diseases. Histological examination demonstrated that aggregates of unrelated amyloidogenic proteins or peptides, including prion protein, tau, Aβ peptides, α-synuclein, immunoglobulin light chain λ, and β2-microglobulin, could be observed within the same plaques or in close proximity [12,13,14,15,16,17]. Could cross-seeding between unrelated amyloidogenic proteins contribute to the etiology of neurodegenerative diseases?
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