Pathogenic Protein Seeding in Alzheimer's Disease and Other Neurodegenerative Disorders

• Type of Material: Article
• Authors: Mathias Jucker, University of Tübingen; Lary C Walker, Emory University
• Language: English
• Date: 2011-10
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 American Neurological Association
• Final Published Version (URL): http://dx.doi.org/10.1002%2Fana.22615
• Title of Journal or Parent Work: Annals of Neurology
• ISSN: 0364-5134
• Volume: 70
• Issue: 4
• Start Page: 532
• End Page: 540
• Grant/Funding Information: Supported by the BMBF in the framework of ERA-Net NEURON (MIPROTRAN), Competence Network on Degenerative Dementias (BMBF-01GI0705), NIH RR-00165, PO1AG026423, P50AG025688, and the CART Foundation.
• Keywords: neurofibrillary tangles; amyloid; tauopathy; inclusions; prion; senile plaques; Parkinson’s disease; proteopathy; amyotrophic lateral sclerosis; Alzheimer’s disease; Huntington’s disease; frontotemporal lobar degeneration
• Research Categories: Biology, Neuroscience

Abstract

The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer’s disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism – corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prion-like induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson’s/Lewy body disease, Huntington’s disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.