Chapter 9 - Membrane Pores in the Pathogenesis of Neurodegenerative Disease

Abstract

The neurodegenerative diseases described in this volume, as well as many nonneurodegenerative diseases, are characterized by deposits known as amyloid. Amyloid has long been associated with these various diseases as a pathological marker and has been implicated directly in the molecular pathogenesis of disease. However, increasing evidence suggests that these proteinaceous Congo red staining deposits may not be toxic or destructive of tissue. Recent studies strongly implicate smaller aggregates of amyloid proteins as the toxic species underlying these neurodegenerative diseases. Despite the outward obvious differences among these clinical syndromes, there are some striking similarities in their molecular pathologies. These include dysregulation of intracellular calcium levels, impairment of mitochondrial function, and the ability of virtually all amyloid peptides to form ion-permeable pores in lipid membranes. Pore formation is enhanced by environmental factors that promote protein aggregation and is inhibited by agents, such as Congo red, which prevent aggregation. Remarkably, the pores formed by a variety of amyloid peptides from neurodegenerative and other diseases share a common set of physiologic properties. These include irreversible insertion of the pores in lipid membranes, formation of heterodisperse pore sizes, inhibition by Congo red of pore formation, blockade of pores by zinc, and a relative lack of ion selectivity and voltage dependence. Although there exists some information about the physical structure of these pores, molecular modeling suggests that 4-6-mer amyloid subunits may assemble into 24-mer pore-forming aggregates. The molecular structure of these pores may resemble the β-barrel structure of the toxics pore formed by bacterial toxins, such as staphylococcal α-hemolysin, anthrax toxin, and Clostridium perfringolysin.