A provocative proposal by biochemistry professor Timothy Foley, Ph.D., based on an extensive review of existing research and results from his own lab, questions a broadly-accepted theory that neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS), are caused by “oxidative stress” and, more specifically, by “free radical”-induced brain damage.
In an article published in Cellular and Molecular Neurobiology, in which he references 158 research studies, Dr. Foley puts forth a new hypothesis. Specifically, he postulates that over-activation of pathways likely designed to protect against oxidative stress may generate an overlooked “reductive stress” – the opposite of oxidative stress – especially in the extracellular spaces of synapses which mediate communication between neurons. Dr. Foley proposes that the increased reduction, or addition of electrons, to regulatory sulfur-containing groups on synaptic membrane proteins, can promote aberrant changes in synaptic activity. He has termed this view the “reductive reprogramming” hypothesis of neurodegeneration.
“The biochemical pathways or reactions that begin to derail healthy brain aging and set the course for neurodegenerative disease remain unknown and, for the last 30 years, the research has focused on reactions that are relevant to advanced stages of the disease,” said Dr. Foley. “One longstanding and dominate theory of neurodegenerative disorders has been that neuron dysfunction and degeneration results from aberrant nutrient and oxygen metabolism resulting in what is called oxidative stress.”
“Oxidation refers to the removal of electrons from form molecules, a process that can potentially damage cells and impair tissue functions,” Dr. Foley said, who theorizes that the oxidative stress may be a secondary phenomenon or a response to another reaction driving the degenerative disease and is insufficient to cause functional impairment.
According to Dr. Foley, the commonly accepted oxidative stress theories of neurodegenerative disorders are “ill-defined and focused primarily on a particular type of oxidant known as “free radicals,” which are substances containing one or more unpaired electrons. Hydrogen peroxide, the most abundant oxidant in cells, is not a free radical and can act as a physiologically-important messenger molecule. He also explained that cells have a high capacity to adapt to elevated levels of oxidants by increasing reducing, or antioxidant, activities.
“Remarkably, oxidative stress theories of neurodegenerative disorders are generally accepted by the scientific and medical communities despite the fact that antioxidant supplements, such as vitamins E and C, neither lower the incidence nor slow the progression of these disorders,” said Dr. Foley noting that one study reported the use of an “antioxidant cocktail” that actually accelerated cognitive decline.
Dr. Foley said new hypotheses of neurodegenerative disorders are needed and, in the article, puts forth his own theory based on research regarding the central role played by protein sulfur atoms as sensors of cellular oxidants and reductants in vivo, a theory that he said is supported by research completed at Scranton, as well as by studies completed elsewhere.
“The reductive reprogramming hypothesis I put forth theorizes that irregular increases in compensatory antioxidant activities in neural tissues may, in principle, promote the aberrant reduction of oxidized protein sulfur on the cell surface of neurons. Oxidized sulfur on certain neuronal cell surface proteins may prevent excessive activity in the extracellular synaptic space which connects the neurons. Reversal of this oxidation by cellular antioxidants can promote synaptic dysfunction and neural cell death by a process called “excitotoxicity” – or over activation of receptors.” said Dr. Foley. “Ironically, increases in cellular reducing activities have been cited as further support for oxidative stress theories of neurodegeneration without considering the possibility that too much reduction of oxidized protein sulfur can be a bad thing.”
The paper, titled “Reductive Reprogramming: A Not-So-Radical Hypothesis of Neurodegeneration Linking Redox Perturbations to Neuroinflammation and Excitotoxicity,” was published online March 23 by Cellular and Molecular Neurobiology.
Dr. Foley’s research, some of which includes University undergraduate and master’s students as co-authors, has been published in a number of academic journals, including Neurochemical Research, Cellular and Molecular Neurobiology and Biochemical and Biophysical Research Communications. He has served as a faculty mentor for numerous students. Several students who conducted research with him have won Goldwater Scholarships, which are the premier undergraduate scholarships for the fields of mathematics, natural sciences and engineering.
Dr. Foley teaches CHEM 550 (Biochemical Structure and Function), 551 (Biocatalysis and Metabolism), and 555 (Chemical Toxicology) in our graduate program.
He also has seven graduate students currently working in his research group.
Learn more about the Chemistry program at The University of Scranton.