Quarterly Reviews of Biophysics



Review Article

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?


Hilal A. Lashuel a1c1 and Peter T. Lansbury Jr. a2c1
a1 Laboratory of Molecular Neurobiology and Neuroproteomics, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
a2 Harvard Center for Neurodegeneration and Repair, Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne St, Cambridge, MA 02139, USA

Article author query
lashuel ha   [PubMed][Google Scholar] 
lansbury pt   [PubMed][Google Scholar] 

Abstract

1. Introduction 2

2. What is the significance of the shared structural properties of disease-associated protein fibrils? 3

2.1 Mechanism of amyloid fibril formation in vitro 6

2.1.1 In vitro fibril formation involves transient population of ordered aggregates of intermediate stability, or protofibrils 6

3. Toxic properties of protofibrils 7

3.1 Protofibrils, rather than fibrils, are likely to be pathogenic 7

3.2 The toxic protofibril may be a mixture of related species 8

3.3 Morphological similarities of protofibrils suggest a common mechanism of toxicity 9

3.4 Are the amyloid diseases a subset of a much larger class of previously unrecognized protofibril diseases? 9

3.5 Fibrils, in the form of aggresomes, may function to sequester toxic protofibrils 9

4. Amyloid pores, a common structural link among protein aggregation neurodegenerative diseases 10

4.1 Mechanistic studies of amyloid fibril formation reveal common features, including pore-like protofibrils 10

4.1.1 Amyloid-β (Aβ) (Alzheimer's disease) 10

4.1.2 α-Synuclein (PD and diffuse Lewy body disease) 12

4.1.3 ABri (familial British dementia) 13

4.1.4 Superoxide dismutase-1 (amyotrophic lateral sclerosis) 13

4.1.5 Prion protein (Creutzfeldt–Jakob disease, bovine spongiform encephalopathy, etc.) 14

4.1.6 Huntingtin (Huntington's disease) 14

4.2 Amyloidogenic proteins that are not linked to disease also from pore-like protofibrils 15

4.3 Amyloid proteins form non-fibrillar aggregates that have properties of protein channels or pores 15

4.3.1 Aβ ‘channels’ 15

4.3.2 α-Synuclein ‘pores’ 16

4.3.3 PrP ‘channels’ 16

4.3.4 Polyglutamine ‘channels’ 17

4.4 Nature uses β-strand-mediated protein oligomerization to construct pore-forming toxins 17

5. Mechanisms of protofibril induced toxicity in protein aggregation diseases 19

5.1 The amyloid pore can explain the age-association and cell-type selectivity of the neurodegenerative diseases 19

5.2 Protofibrils may promote their own accumulation by inhibiting the proteasome 20

6. Testing the amyloid pore hypothesis by attempting to disprove it 21

7. Acknowledgments 22

8. References 22

Protein fibrillization is implicated in the pathogenesis of most, if not all, age-associated neurodegenerative diseases, but the mechanism(s) by which it triggers neuronal death is unknown. Reductionist in vitro studies suggest that the amyloid protofibril may be the toxic species and that it may amplify itself by inhibiting proteasome-dependent protein degradation. Although its pathogenic target has not been identified, the properties of the protofibril suggest that neurons could be killed by unregulated membrane permeabilization, possibly by a type of protofibril referred to here as the ‘amyloid pore’. The purpose of this review is to summarize the existing supportive circumstantial evidence and to stimulate further studies designed to test the validity of this hypothesis.

(Published Online September 18 2006)


Correspondence:
c1 Email: hilal.lashuel@epfl.ch or plansbury@rics.bwh.harvard.edu