Focus Quality Control
- The EMBO Journal (2008) 27, 336 - 349
- doi:10.1038/sj.emboj.7601930
Subject Categories:
The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases
Konstanze F Winklhofer1, Jörg Tatzelt1 and Christian Haass2
- Neurobiochemisty, Department of Biochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany
- Center for Integrated Protein Science Munich and Laboratory for Neurodegenerative Disease Research, Department of Biochemistry, Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Munich, Germany
Correspondence to:
Konstanze F Winklhofer, 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@med.uni-muenchen.de
Christian Haass, 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@med.uni-muenchen.de
Received 14 August 2007; Accepted 24 October 2007
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.
Keywords:
- Alzheimer,
- FTLD,
- misfolding,
- Parkinson,
- prion
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
NEWS AND VIEWS
Pathological tau: a loss of normal function or a gain in toxicity?
Nature Neuroscience News and Views (01 Sep 2005)
Protofibrils, the unifying toxic molecule of neurodegenerative disorders?
Nature Neuroscience News and Views (01 Sep 2001)
Towards an understanding of amyloidogenesis
Nature Structural Biology News and Views (01 May 2002)
Alzheimer's disease Moving towards a vaccine
Nature News and Views (24 Jul 2008)
Nature Medicine News and Views (01 Apr 2004)
