Abstract
Conformational changes in amyloidogenic proteins, such as β-amyloid protein, prion proteins, and α-synuclein, play a critical role in the pathogenesis of numerous neurodegenerative diseases, including Alzheimer’s disease, prion disease, and Lewy body disease. The disease-associated proteins possess several common characteristics, including the ability to form amyloid oligomers with β-pleated sheet structure, as well as cytotoxicity, although they differ in amino acid sequence. Interestingly, these amyloidogenic proteins all possess the ability to bind trace metals, can regulate metal homeostasis, and are co-localized at the synapse, where metals are abundantly present. In this review, we discuss the physiological roles of these amyloidogenic proteins in metal homeostasis, and we propose hypothetical models of their pathogenetic role in the neurodegenerative process as the loss of normal metal regulatory functions of amyloidogenic proteins. Notably, these amyloidogenic proteins have the capacity to form Ca2+-permeable pores in membranes, suggestive of a toxic gain of function. Therefore, we focus on their potential role in the disruption of Ca2+ homeostasis in amyloid-associated neurodegenerative diseases.
Highlights
The oligomerization of proteins affects their conformation, shape, and function
The loss of normal functions of amyloidogenic proteins causes the disruption of metal homeostasis, resulting in neurodegeneration
The conformational change in amyloidogenic proteins and the formation of unregulated Ca2+ channels is a gain of toxic function
Summary
The oligomerization of proteins affects their conformation, shape, and function. The concept of conformational diseases (or protein misfolding diseases), highlighting the importance of protein conformational changes in the pathogenesis of disease, was first proposed in 1997 [1], and has been supported by recent studies [2,3]. We hypothesized that the loss of normal metal regulatory functions may be involved in the pathogenesis of AD, prion diseases, and Lewy body diseases [13]. Based on this perspective, we review current studies on the role of these proteins in neurodegenerative diseases. Dyshomeostasis by forming channel-like pores in membranes We hypothesize that this gain of toxic function of amyloid oligomers may be a common neurodegenerative mechanism in amyloidsis [14]. We discuss the importance of lipid–metal, metal–protein, and lipid–protein crosstalk in this review article These dual neurodegenerative mechanisms highlight the potential contribution of metals in the pathogenesis of AD, prion diseases, and Lewy body diseases. They may serve as key targets for drug development for these neurodegenerative diseases
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