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Interactions of pathological proteins in neurodegenerative diseases

Lookup NU author(s): Professor Johannes Attems



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2017 The Author(s) Neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTD), Lewy body disease (LBD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) have in common that protein aggregates represent pathological hallmark lesions. Amyloid β-protein, τ-protein, α-synuclein, and TDP-43 are the most frequently aggregated proteins in these disorders. Although they are assumed to form disease-characteristic aggregates, such as amyloid plaques and neurofibrillary tangles in AD or Lewy bodies in LBD/PD, they are not restricted to these clinical presentations. They also occur in non-diseased individuals and can co-exist in the same brain without or with a clinical picture of a distinct dementing or movement disorder. In this review, we discuss the co-existence of these pathologies and potential additive effects in the human brain as well as related functional findings on cross-seeding and molecular interactions between these aggregates/proteins. We conclude that there is evidence for interactions at the molecular level as well as for additive effects on brain damage by multiple pathologies occurring in different functionally important neurons. Based upon this information, we hypothesize a cascade of events that may explain general mechanisms in the development of neurodegenerative disorders: (1) distinct lesions are a prerequisite for the development of a distinct disease (e.g., primary age-related tauopathy for AD), (2) disease-specific pathogenic events further trigger the development of a specific disease (e.g., Aβ aggregation in AD that exaggerate further Aβ and AD-related τ pathology), (3) the symptomatic disease manifests, and (4) neurodegenerative co-pathologies may be either purely coincidental or (more likely) have influence on the disease development and/or its clinical presentation.

Publication metadata

Author(s): Spires-Jones TL, Attems J, Thal DR

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica

Year: 2017

Volume: 134

Issue: 2

Pages: 187-205

Print publication date: 01/08/2017

Online publication date: 11/04/2017

Acceptance date: 01/04/2017

Date deposited: 02/05/2017

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer Verlag


DOI: 10.1007/s00401-017-1709-7


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