Membrane Permeabilization: A Common Mechanism in Protein-Misfolding Diseases

Abstract

Protein aggregation--and, more specifically, amyloid fibril formation--has been implicated as a primary cause of neurodegeneration in Alzheimer's disease, Parkinson's disease, and related disorders, but the mechanism by which this process triggers neuronal death is unknown. Mounting evidence from in vitro studies, cell culture, and animal models of these diseases supports the hypothesis that a structural intermediate on the pathway to fibril formation, rather than amyloid fibrils themselves, may be the pathogenic species. Characterization of these intermediates in solution or upon interactions with membranes indicate that these intermediates form pores and suggests that neurons could be killed by unregulated membrane permeabilization caused by such "amyloid pores."