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Amyloid fibril polymorphism - a challenge for molecular imaging and therapy

Authors
  • Fändrich, Marcus1
  • Nyström, Sofie2
  • Nilsson, K. Peter R.2
  • Böckmann, Anja3
  • LeVine, Harry III4
  • Hammarström, Per2
  • 1 Institute of Protein Biochemistry, Ulm University, Ulm, Germany
  • 2 Department of Physics, Chemistry and Biology, division of Chemistry, Linköping University, Linköping, Sweden
  • 3 Lyon, 7 passage du Vercors, 69367 Lyon, France
  • 4 Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA
Type
Published Article
Journal
Journal of internal medicine
Publication Date
Feb 19, 2018
Volume
283
Issue
3
Pages
218–237
Identifiers
DOI: 10.1111/joim.12732
PMID: 29360284
PMCID: PMC5820168
Source
PubMed Central
Keywords
License
Unknown

Abstract

The accumulation of misfolded proteins (MP), both unique and common, for different diseases is central for many chronic degenerative diseases. In certain patients MP accumulation is systemic (e.g. TTR amyloid) and in others this is localized to a specific cell type (e.g. Alzheimer’s disease). In neurodegenerative diseases, NDs, it is noticeable that the accumulation of MP progressively spreads throughout the nervous system. Our main hypothesis of this article is that MPs are not only markers but also active carriers of pathogenicity. Here, we discuss studies from comprehensive molecular approaches aimed at understanding MP conformational variations (polymorphism) and their bearing on spreading of MPs, MP toxicity, as well as MP targeting in imaging and therapy. Neurodegenerative disease (ND) represents a major and growing societal challenge, with millions of people worldwide suffering from Alzheimer’s or Parkinson’s diseases alone. For all NDs, current treatment is palliative without addressing the primary cause, and is not curative. Over recent years particularly the shape-shifting properties of misfolded proteins and their spreading pathways have been intensively researched. The difficulty in addressing ND has prompted most major pharma companies to severely downsize their nervous system disorder research. Increased academic research is pivotal for filling this void and to translate basic research into tools for medical professionals. Recent discoveries of targeting drug design against MPs and improved model systems to study structure, pathology spreading and toxicity strongly encourage future studies along these lines to provide an opportunity for selective imaging, prognostic diagnosis, and therapy.

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