Neurodegeneration and peroxidases

Abstract 

Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that affect different parts of the central nervous system. However, a review of the literature indicates that certain biochemical reactions involved in neurodegeneration in these three diseases are quite similar and could be partly identical. This article critically examines the similarities and, based on data from our own and other laboratories, proposes a novel explanation for neurodegeneration in these three diseases.

We identified about 20 commonalities that exist in the neurodegenerative process of each disease. We hypothesize that there are two enzyme-catalyzed pathways that operate in affected neurons: an oxidative pathway leading to destruction of various neuronal proteins and lipids, and an apoptotic pathway which the body normally uses to remove unwanted and dysfunctional cells. Data from many laboratories indicate that oxidative reactions are primarily responsible for neurodegeneration, whereas apoptosis may well be a secondary response to the presence of neurons that have already been severely damaged by oxidative reactions. Attempts to inhibit apoptosis for the purpose of attenuating progression of these diseases may therefore be only of marginal benefit.

Specific oxidative reactions within affected neurons led us to propose that one or more heme peroxidases may be the catalyst(s) involved in oxidation of proteins and lipids. Support for this proposal is provided by the recent finding that amyloi-β peptide may act as a peroxidase in AD. Possible participation of the peroxidase activity of cytochrome c, herein designated as cytochrome c_px to distinguish it from yeast cytochrome c peroxidase, is discussed. Of special interest is our recent finding that many compounds that cause attenuation of neurodegeneration are inhibitors of the peroxidase activity of cytochrome c. Several inhibitors were subsequently identified as suicide substrates. Such inhibitors could be ideally suited for targeted clinical approaches aimed at arresting progression of neurodegeneration.

Finally, it is possible that immobilized yet still active peroxidase(s) may be present in protein aggregates in AD, PD, and ALS. This activity could be the catalyst for the slow, self-perpetuating and irreversible degeneration of affected neurons that occurs over long periods of time in these neurodegenerative diseases.

Keywords: Neurodegeneration, Peroxidases, Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Biochemistry of neurodegeneration, Oxidative damage, Apoptosis, Cytochrome c