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The two faces of protein misfolding: gain‐ and loss‐of‐function in neurodegenerative diseases

Konstanze F Winklhofer, Jörg Tatzelt, Christian Haass

Author Affiliations

  1. Konstanze F Winklhofer*,1,
  2. Jörg Tatzelt1 and
  3. Christian Haass*,2
  1. 1 Neurobiochemisty, Department of Biochemistry, Adolf‐Butenandt‐Institute, Ludwig‐Maximilians‐University, Munich, Germany
  2. 2 Center for Integrated Protein Science Munich and Laboratory for Neurodegenerative Disease Research, Department of Biochemistry, Adolf‐Butenandt‐Institute, Ludwig‐Maximilians‐University, Munich, Germany
  1. *Corresponding authors: Neurobiochemistry, Department of Biochemistry, Adolf‐Butenandt‐Institute, Ludwig‐Maximilians‐University, Munich 80336, Germany. Tel.: +49 89 2180 75 483; Fax: +49 89 2180 75 415; E-mail: konstanze.winklhofer{at}med.uni-muenchen.de Center for Integrated Protein Science Munich and Laboratory for Neurodegenerative Disease Research, Department of Biochemistry, Adolf‐Butenandt‐Institute, Ludwig‐Maximilians‐University, Munich 80336, Germany. Tel.: +49 89 2180 75 480/472; Fax: +49 89 2180 75 415; E-mail: chaass{at}med.uni-muenchen.de
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Abstract

The etiologies of neurodegenerative diseases may be diverse; however, a common pathological denominator is the formation of aberrant protein conformers and the occurrence of pathognomonic proteinaceous deposits. Different approaches coming from neuropathology, genetics, animal modeling and biophysics have established a crucial role of protein misfolding in the pathogenic process. However, there is an ongoing debate about the nature of the harmful proteinaceous species and how toxic conformers selectively damage neuronal populations. Increasing evidence indicates that soluble oligomers are associated with early pathological alterations, and strikingly, oligomeric assemblies of different disease‐associated proteins may share common structural features. A major step towards the understanding of mechanisms implicated in neuronal degeneration is the identification of genes, which are responsible for familial variants of neurodegenerative diseases. Studies based on these disease‐associated genes illuminated the two faces of protein misfolding in neurodegeneration: a gain of toxic function and a loss of physiological function, which can even occur in combination. Here, we summarize how these two faces of protein misfolding contribute to the pathomechanisms of Alzheimer's disease, frontotemporal lobar degeneration, Parkinson's disease and prion diseases.

  • Received August 14, 2007.
  • Accepted October 24, 2007.
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