Membrane protein oxidation determines neuronal degeneration.
Oxidative stress is an early hallmark in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. However, the critical biochemical effector mechanisms of oxidative neurotoxicity have remained surprisingly elusive. In screening various peroxides and potential substrates of oxidation for their effect on neuronal survival, we observed that intramembrane compounds were significantly more active than aqueous or amphiphilic compounds. To better understand this result, we synthesized a series of competitive and site-specific membrane protein oxidation inhibitors termed aminoacyllipids, whose structures were designed on the basis of amino acids frequently found at the protein-lipid interface of synaptic membrane proteins. Investigating the aminoacyllipids in primary neuronal culture, we found that the targeted protection of transmembrane tyrosine and tryptophan residues was sufficient to prevent neurotoxicity evoked by hydroperoxides, kainic acid, glutathione-depleting drugs, and certain amyloidogenic peptides, but ineffective against non-oxidative inducers of apoptosis such as sphingosine or Akt kinase inhibitors. Thus, the oxidative component of different neurotoxins appears to converge on neuronal membrane proteins, irrespective of the primary mechanism of cellular oxidant generation. Our results indicate the existence of a one-electron redox cycle based on membrane protein aromatic surface amino acids, whose disturbance or overload leads to excessive membrane protein oxidation and neuronal death. Membrane proteins have rarely been investigated as potential victims of oxidative stress in the context of neurodegeneration. This study provides evidence that excessive one-electron oxidation of membrane proteins from within the lipid bilayer, depicted in the graphic, is a functionally decisive step toward neuronal cell death in response to different toxins.
Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Parvana
P
Hajieva
Nadhim
N
Bayatti
Matthias
M
Granold
Christian
C
Behl
Bernd
B
Moosmann
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
D008565:Membrane Proteins; D017382:Reactive Oxygen Species
Alzheimer's disease; membrane protein; neurodegeneration; neurotoxicity; protein oxidation; redox cycling