Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases

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Many neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, are characterized by the progressive appearance of abnormal proteinaceous assemblies in the nervous system. Studies in experimental systems indicate that the assemblies originate from the prion-like seeded aggregation of specific misfolded proteins that proliferate and amass to form the intracellular and/or extracellular lesions typical of each disorder. The host in which the proteopathic seeds arise provides the biochemical and physiological environment that either supports or restricts their emergence, proliferation, self-assembly, and spread. Multiple mechanisms influence the spatiotemporal spread of seeds and the nature of the resulting lesions, one of which is the cellular uptake, release, and transport of seeds along neural pathways and networks. The characteristics of cells and regions in the affected network govern their vulnerability and thereby influence the neuropathological and clinical attributes of the disease. The propagation of pathogenic protein assemblies within the nervous system is thus determined by the interaction of the proteopathic agent and the host milieu.

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Fig. 1: Factors governing the genesis, replication, and spread of proteopathic seeds.
Fig. 2: Compatibility of seed and cognate host protein regulates the propagation of proteopathic seeds at the organismic level.
Fig. 3: Compatibility of seed and cognate cellular protein governs propagation at the cellular or compartmental level.


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We thank J. Rasmussen, M. Bacioglu, and the members of our laboratories for critical discussions and comments. The help of A. Apel and G. Rose with the manuscript and figures is gratefully acknowledged. Supported by the EC Joint Programme on Neurodegenerative Diseases under the Grants JPND-NewTargets and JPND-REfrAME (M.J.), Horizon 2020 IMPRiND (M.J.), National Institutes of Health (NIH) grants P50 AG025688 and ORIP/OD P51OD011132, and by the Alexander von Humboldt Foundation (L.C.W.).

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Correspondence to Mathias Jucker or Lary C. Walker.

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