Amyloids: Regulators of Metal Homeostasis in the Synapse

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.

Neurometals in the Pathogenesis of Prion Diseases

“…These findings strongly suggest the “amyloid channel hypothesis”, namely that the disruption of Ca homeostasis via the upregulation of amyloid channels may be the molecular basis of the neurotoxicity of prion and other conformational diseases [ 14 , 112 ]. Furthermore, metals such as Zn and/or Cu are also implicated in the functions of these amyloid channels.…”

“…We found that AβP, human amylin, and NAC also caused increases in [Ca 2+ ] i similar to PrP106–126. PrP106–126, AβP, and human amylin caused the perforation of liposome membranes [ 14 , 107 ]. Meanwhile, it is possible that PrP C regulates Ca 2+ homeostasis because PrP-null mice exhibited alterations of Ca 2+ buffering and [Ca 2+ ] i [ 108 ].…”

“…Interestingly, PrP C , APP, and α-synuclein are co-localized at the synapse, which is a narrow space filled with metals and the major target of these neurodegenerative diseases. APP and α-synuclein also possess metal-binding abilities and are involved in the regulation of metal homeostasis [ 14 ].…”

Carnosine as a Possible Drug for Zinc-Induced Neurotoxicity and Vascular Dementia

“…Synaptic Cu 2+ is also released to the synaptic clefts during neuronal excitation and bind to NMDA-type glutamate receptors, to regulate synaptic functions as well as Zn 2+ . Therefore, crosstalk between Zn 2+ and Cu 2+ plays important roles in physiological and pathophysiological functions in the brain [37].…”

Iron enhances the binding rates and translational efficiency of iron responsive elements (IREs) mRNA with initiation factor eIF4F

“…Elevated cellular iron levels can interrupt IRP/IRE binding, and promote translation of the ferritin and ferroportin in a way that destabilizes divalent metal transporter and transferrin receptor mRNA [6]. Therefore, disturbance of the IRP/ IRE signaling pathway caused by the elevated iron levels impairs iron homeostasis, thereby contributing to the protein aggregation and neuronal loss observed in Alzheimer's and Parkinson's diseases [13,14]. The implicated proteins misfold, causing fibrils to form that propagate across neurons in the brain.…”