Abstract
Metal ions are key elements in organisms' life acting like cofactors of many enzymes but they can also be potentially dangerous for the cell participating in redox reactions that lead to the formation of reactive oxygen species (ROS). Any factor inducing or limiting a metal dyshomeostasis, ROS production and cell injury may contribute to the onset of neurodegenerative diseases or play a neuroprotective action. Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of fatal neurodegenerative disorders affecting the central nervous system (CNS) of human and other mammalian species. The causative agent of TSEs is believed to be the scrapie prion protein PrPSc, the β sheet-rich pathogenic isoform produced by the conformational conversion of the α-helix-rich physiological isoform PrPC. The peculiarity of PrPSc is its ability to self-propagate in exponential fashion in cells and its tendency to precipitate in insoluble and protease-resistance amyloid aggregates leading to neuronal cell death. The expression “prion-like diseases” refers to a group of neurodegenerative diseases that share some neuropathological features with prion diseases such as the involvement of proteins (α-synuclein, amyloid β, and tau) able to precipitate producing amyloid deposits following conformational change. High social impact diseases such as Alzheimer's and Parkinson's belong to prion-like diseases. Accumulating evidence suggests that the exposure to environmental metals is a risk factor for the development of prion and prion-like diseases and that metal ions can directly bind to prion and prion-like proteins affecting the amount of amyloid aggregates. The diet, source of metal ions but also of natural antioxidant and chelating agents such as polyphenols, is an aspect to take into account in addressing the issue of neurodegeneration. Epidemiological data suggest that the Mediterranean diet, based on the abundant consumption of fresh vegetables and on low intake of meat, could play a preventive or delaying role in prion and prion-like neurodegenerative diseases. In this review, metal role in the onset of prion and prion-like diseases is dealt with from a nutritional, cellular, and molecular point of view.
Highlights
Many neurodegenerative diseases such as Alzheimer’s disease (AD), synucleinopathies, Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia can be included under the definition of “prion-like disease” as they share some neuropathological features with the prion diseases
Α-syn and prion-like proteins (Aβ and tau) can directly interact with several metal ions affecting the conformation of the protein and its tendency to aggregate in oligomers and fibrils
Since transition metal and iron have been clearly involved in neurodegenerative disorders and aging (Ward et al, 2014), we focus on the free radical scavenging and metal chelation effects of some polyphenols
Summary
Many neurodegenerative diseases such as Alzheimer’s disease (AD), synucleinopathies (including Parkinson’s disease, PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia can be included under the definition of “prion-like disease” as they share some neuropathological features with the prion diseases (transmissible spongiform encephalopathies, TSEs). The radical-mediated oxidation of a protein can strongly affect its molecular structure by the generation of protein-protein linkages, the oxidation of amino acid side chains and even by the fragmentation of the polypeptide chain and the level of oxidized proteins increases during aging in many animals (for detail refer to Stadtman, 2006; Valensin et al, 2016) For this reason, in the CNS any factor which induces a metal dyshomeostasis and the consequent production of ROS and cell injury may contribute to the onset of these neurodegenerative diseases. Any factor able to reduce metal dyshomeostasis and to limit the production of ROS and free radicals can play a neuroprotective action In addition to these general aspects, metal ions can have a more direct involvement in prion and prion-like neurodegenerative diseases for their ability to directly bind to prion and prion-like proteins and to affect the amount of amyloid aggregates. Metal role in the onset of prion diseases (TSEs and synucleinopathies) and in AD, as an example of prion-like disease, is dealt with from a nutritional, cellular and molecular point of view
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