Copper Homeostasis and Neurodegenerative Disorders (Alzheimer's, Prion, and Parkinson's Diseases and Amyotrophic Lateral Sclerosis)

Oxidative stress is known to play an important role in the pathogenesis of a number of diseases. In particular, it is linked to the etiology of Alzheimer's disease (AD), an age-related neurodegenerative disease and the most common cause of dementia in the elderly. Histopathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular formation of senile plaques composed of the amyloid-beta peptide (Aβ) in aggregated form along with metal-ions such as copper, iron or zinc. Redox active metal ions, as for example copper, can catalyze the production of Reactive Oxygen Species (ROS) when bound to the amyloid-β (Aβ). The ROS thus produced, in particular the hydroxyl radical which is the most reactive one, may contribute to oxidative damage on both the Aβ peptide itself and on surrounding molecule (proteins, lipids, …). This review highlights the existing link between oxidative stress and AD, and the consequences towards the Aβ peptide and surrounding molecules in terms of oxidative damage. In addition, the implication of metal ions in AD, their interaction with the Aβ peptide and redox properties leading to ROS production are discussed, along with both in vitro and in vivo oxidation of the Aβ peptide, at the molecular level.

https://hal.archives-ouvertes.fr/hal-01635507/document

Oxidative stress and the amyloid beta peptide in Alzheimer's disease.

Purpose of review Epigenetics investigates heritable changes in gene expression occurring without changes in DNA sequence. Several epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA expression, can change genome function under exogenous influence. Here, we review current evidence indicating that epigenetic alterations mediate toxicity from environmental chemicals. Recent findings In-vitro, animal, and human investigations have identified several classes of environmental chemicals that modify epigenetic marks, including metals (cadmium, arsenic, nickel, chromium, and methylmercury), peroxisome proliferators (trichloroethylene, dichloroacetic acid, and TCA), air pollutants (particulate matter, black carbon, and benzene), and endocrine-disrupting/reproductive toxicants (diethylstilbestrol, bisphenol A, persistent organic pollutants, and dioxin). Most studies conducted so far have been centered on DNA methylation, whereas only a few investigations have studied environmental chemicals in relation to histone modifications and microRNA. Summary For several exposures, it has been proved that chemicals can alter epigenetic marks, and that the same or similar epigenetic alterations can be found in patients with the disease of concern or in diseased tissues. Future prospective investigations are needed to determine whether exposed individuals develop epigenetic alterations over time and, in turn, which such alterations increase the risk of disease. Also, further research is needed to determine whether environmental epigenetic changes are transmitted transgenerationally.

Epigenetics and environmental chemicals.

Chronic exposure to nickel(II), chromium(VI), or inorganic arsenic (iAs) has long been known to increase cancer incidence among affected individuals. Recent epidemiological studies have found that carcinogenic risks associated with chromate and iAs exposures were substantially higher than previously thought, which led to major revisions of the federal standards regulating ambient and drinking water levels. Genotoxic effects of Cr(VI) and iAs are strongly influenced by their intracellular metabolism, which creates several reactive intermediates and byproducts. Toxic metals are capable of potent and surprisingly selective activation of stress-signaling pathways, which are known to contribute to the development of human cancers. Depending on the metal, ascorbate (vitamin C) has been found to act either as a strong enhancer or suppressor of toxic responses in human cells. In addition to genetic damage via both oxidative and nonoxidative (DNA adducts) mechanisms, metals can also cause significant changes in DNA methylation and histone modifications, leading to epigenetic silencing or reactivation of gene expression. In vitro genotoxicity experiments and recent animal carcinogenicity studies provided strong support for the idea that metals can act as cocarcinogens in combination with nonmetal carcinogens. Cocarcinogenic and comutagenic effects of metals are likely to stem from their ability to interfere with DNA repair processes. Overall, metal carcinogenesis appears to require the formation of specific metal complexes, chromosomal damage, and activation of signal transduction pathways promoting survival and expansion of genetically/epigenetically altered cells.

http://pubs.acs.org/doi/pdf/10.1021/tx700198a

Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium.

ion of hydrogen from the γ-(C-4) carbon of aliphatic side chains in the presence of oxygen can yield C-2 -C-3 dehydropeptides, via the formation of peroxyl radicals from the γ-carbon-centered radical. 208,210 For example, in the oxidation of the Glu side chain, the γ-carbon peroxyl radical may undergo subsequent reactions leading to the formation of side chain modification products with a mass shift of -30 Da due to decarboxylation; 209,211+14 and+16 Da products; or an unsaturated product, a C-2 -C-3 dehydropeptide (Scheme 4). The dehydropeptide behaves like an oxygenated enol species, which readily undergoes tautomerism to the keto form. This species is easily hydrolyzed to yield two protein fragments: a new amide and a keto acid. 210 Oxidation of aspartic acid seems similar to the case of Glu and may also result in the cleavage of the protein backbone 212 or decarboxylation of a side chain carboxyl group, 211 except at a lower rate than that for Glu. 211 3.2.4. Main Chain Cleavage via Radical Transfer from the â-Carbon at Side Chains Initial hydroxyl radical attack at theâ-carbon (C-3) position can lead to the formation of R-carbon radicals and subsequent main chain rupture. 213,214 In this case, alkoxyl radicals are generated after initial H-abstraction to produce carbon-centered radicals and subsequent reaction with O 2 o give peroxyl radicals (Scheme 5). A number of different pathways may generate alkoxyl radical from different precursors, including termination reactions of the peroxyl species with other radicals and decomposition of the intermediate hydroperoxides. 215,216The alkoxyl radicals can undergoâ-scission at a rate >107 s-1, leading to the loss of a side chain and/or generation of R-carbon radicals and subsequent backbone cleavage. 213,214 The â-scission reaction of alkoxyl radicals appears to be common for aliphatic side chains such as Val, Leu, and Asp,214 resulting in the release of a family of carbonyls including formaldehyde, acetone, isobutyraldehyde, and glyoxylic acids. The rate of suchâ-scission reactions is affected by the nature of the substituents, R and R ′, with the rate of fragmentation increased by the presence of electron releasing alkyl groups and substituents that can stabilize the incipient radical center. The R-carbon radicals generated by the â-scission reaction of alkoxyl radicals are stable due to the delocalization of unpaired electrons onto the neighboring carbonyl and amide functions and relief of steric strain in the alkoxyl radical. 217 Scheme 3. Backbone Cleavage and Side Chain Modification of Pro Hydroxyl Radical-Mediated Modification of Proteins Chemical Reviews, 2007, Vol. 107, No. 8 3527

Hydroxyl radical-mediated modification of proteins as probes for structural proteomics.

http://marcindyba.com/wp-content/uploads/publications/M_Dyba-Coord_Chem_Rev_1999_184_319-346.pdf

Specific structure–stability relations in metallopeptides

Coordination abilities of the 1-16 and 1-28 fragments of β-amyloid peptide towards copper(II) ions: a combined potentiometric and spectroscopic study

Chemical and biological aspects of Cu2+ interactions with peptides and aminoglycosides

Interaction of Ni(II) and Cu(II) with a metal binding sequence of histone H4: AKRHRK, a model of the H4 tail.

http://marcindyba.com/wp-content/uploads/publications/M_Dyba-J_Inorg_Biochem_2004_98_6_940-950.pdf

Teresa Kowalik-Jankowska

Papers

Specific structure–stability relations in metallopeptides

Coordination abilities of the 1-16 and 1-28 fragments of β-amyloid peptide towards copper(II) ions: a combined potentiometric and spectroscopic study

Chemical and biological aspects of Cu2+ interactions with peptides and aminoglycosides

Interaction of Ni(II) and Cu(II) with a metal binding sequence of histone H4: AKRHRK, a model of the H4 tail.

Products of Cu(II)-catalyzed oxidation in the presence of hydrogen peroxide of the 1-10, 1-16 fragments of human and mouse β-amyloid peptide