Functional Amyloid Formation within Mammalian Tissue

Abstract

Amyloid is a generally insoluble, fibrous cross-β sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin—a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin) may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.

Cystatin-related epididymal spermatogenic subgroup members are part of an amyloid matrix and associated with extracellular vesicles in the mouse epididymal lumen

“…Several cellular mechanisms have been proposed to regulate functional amyloid assembly to avoid or minimize exposure of the cell to intermediate, oligomeric forms of amyloid that can be cytotoxic (Bucciantini et al, 2002). These mechanisms include restricting amyloidogenesis to within organelles such as secretory granules or melanosomes, the requirement for proprotein processing to trigger amyloidogenesis or interactions of related proteins to control fibril assembly, as occurs in Escherichia coli (Fowler et al, 2006;Wang and Chapman, 2008;Maji et al, 2009). The bacterial curli proteins determine when and where amyloidogenesis occurs since the CsgB amyloid functions as a nucleator on the cell surface that triggers the soluble CsgA protein to assemble into amyloid allowing the formation of an extracellular matrix (Chapman et al, 2002;Wang and Chapman, 2008).…”

“…Accumulating evidence, however, has established that some proteins self-assemble into amyloid fibrils that carry out biological roles in the absence of pathology and are known as functional amyloids (Fowler et al, 2007;Pham et al, 2014). In mammals, these include premelanosome protein (PMEL), whose amyloid functions as a scaffold for the synthesis of melanin, several hormones that are stored as amyloids in the pituitary gland, RIP1 and RIP3 (receptor-interacting proteins 1 and 3) amyloids involved in programmed necrosis and α-defensin that forms an amyloid net in the gut mucosa for trapping bacteria (Fowler et al, 2006;Maji et al, 2009;Chu et al, 2012;Li et al, 2012). In addition to our studies of CRES amyloid in the epididymal lumen, we have previously shown that the mouse egg zona pellucida is an amyloid, as is part of the mouse sperm acrosomal matrix, demonstrating that functional amyloids are a normal component of the reproductive tract with integral roles in sperm maturation and fertilization (Guyonnet et al, 2014;Egge et al, 2015).…”

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

“…b Mechanistic model of intervention. Monomer dissociation exceeds growth in pre-nuclear assemblies (i), compound binding stabilizes early fibrillar aggregation intermediates and inhibits monomer dissociation (ii) polymerization, forms fibrils much more rapidly that disease-associated proteins [128]. While the toxicity of oligomeric forms of Aβ has been established in multiple experiments in vitro [32,51,129], their role in pathogenesis in vivo is much less understood.…”

The genetics of the amyloidoses: interactions with immunity and inflammation

“…Several examples have now been described in which the amyloid structure serves an apparently normal physiologic function, notably the curli protein of escherichia coli, yeast prions and the melanosome melanin binding protein Pmel17. [13][14][15] Our discussions in this review will cover only those conditions in which tissue deposits fulfilling the pathologic criteria for amyloid, that is, Congophilia, ultrastructurally fibrillar, co-deposited SAP, ApoE and Perlecan, are found. For the most part the deposits are extracellular, although there are now instances in which it has been reported that the earliest steps in aggregation can be seen intracellularly.…”