. Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest. 2007 Jan;117(1):236-45. PubMed.

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  1. By Raj Ratan and Brett Langley.

    Since the discovery of SOD in the late 1960s, enormous attention has been focused on free radicals as endogenous perpetrators of much that ails us, including aging and neurodegeneration. Free radicals can be neutralized by antioxidants such as vitamin E, and the abundance of these substances in some foods in our diets made them natural choices as “pharmacological” cures for both aging and age-related neurodegeneration. Unfortunately, antioxidant neurotherapeutics have been disappointing in clinical trials of a number of diseases including Alzheimer’s and stroke (see results of recent SAINT II trial). These failures reflect, in part, the absence of good in-vivo models in which to study and refine our understanding of an optimal antioxidant strategy.

    This paper by Mel Feany and colleagues, in describing a role for oxidative stress in tau-induced neurodegeneration in Drosophila, describes a model that may be quite useful in advancing the search for antioxidant therapies for AD. Briefly, the team used a number of distinct approaches to demonstrate that genetic or pharmacological manipulation of antioxidant defenses can worsen (if antioxidant enzymes are mutated or deleted) or ameliorate (if antioxidant enzymes are augmented) pathology in a fly model of human tauopathies. The results are compelling. They suggest that reduction in antioxidant defenses, whose common link is the mitochondria (thioredoxin and SOD2 both act in mitochondria), leads to increased cell-autonomous neuronal death due to overexpression of mutant tau. These effects are mimicked by addition of vitamin E.

    In nature, eight substances have been found to have vitamin E activity: α, β, γ, and δ tocopherol; and α, β, γ and δ tocotrienol (Sen et al., 2006). Scientists and clinicians have largely ignored the non-tocopherol vitamin E molecules because α tocopherol is the dominant substance in the human body. Several converging lines of inquiry suggest that members of the vitamin E family are not redundant in their antioxidant-dependent and -independent neuroprotective effects. Indeed, tocotrienol, not tocopherol, prevents neurodegeneration in the nanomolar range. It would thus be quite interesting to determine what is the exact chemical composition of the vitamin E utilized by the Feany group and, if tocopherol is dominant, whether a form of vitamin E enriched in tocotrienol would be more potent and more effective in their exciting model. Such studies could have profound clinical implications.

    From their elegant studies, the authors develop an intriguing model for cell loss in inherited dementias that is congruent with data from sporadic forms of human Alzheimer’s published by Karl Herrup or Inez Vincent’s groups during the past decade. Specifically, the model proposes that mutant forms of tau induce oxidative stress and thereby trigger the aberrant re-entry of postmitotic neurons into the cell cycle. The sad result of this sequence of events is mitotic catastrophe or apoptosis.

    For the most part, the data provided strongly support this model. An important missing link in the model, however, is the demonstration that mutant tau alone causes “oxidative stress.” One of the major challenges for free radical biologists has been to identify early markers of a change in redox state within the cell. Many of the markers discussed by Feany’s group, such as oxidative damage to proteins, DNA, or lipids, may be tombstones that are observed only well after the cells are “committed” to die. It would have been interesting for the group to examine whether transcription factors known to be activated by a redox change such as nrf2 or Sp1 are activated in neurons or glia in regions where neurodegeneration occurs. The nuclear levels of these transcription factors have been shown to increase in glia or neurons in response to depletion of antioxidant defenses or addition of peroxide in vitro or in vivo in brains exposed to mitochondrial toxins or mutant huntingtin protein.

    In the absence of data suggesting that mutant tau induces oxidative stress, another model can be proposed: Mutant tau leads to the inappropriate activation of the cell cycle, leading to apoptosis. Free radicals act upstream or in parallel to increase the propensity of mutant tau to activate death pathways. This model would be consistent with emerging in-vitro data from several groups that oxidative stress is indeed not sufficient to activate aberrant cell cycle events as it triggers cell death. It would be quite interesting if the Feany group determined whether paraquat-induced injury in flies can be prevented by forced expression of dominant-negative forms of cyclin-dependent kinases or pharmacological treatment with inhibitors of cyclin-dependent kinases such as roscovitine or olomucine. Both of these strategies have been shown to prevent death in vitro and in vivo in models of DNA damage, cerebral ischemia, or Parkinson disease.

    In conclusion, the current study adds to the growing stature of the Feany lab as leaders in using fly models to elucidate mechanisms of neurodegeneration in vivo. Our hope is that it will not be long before these exciting findings distill into novel treatments for inherited and sporadic dementias.

    References:

    . Tocotrienols: Vitamin E beyond tocopherols. Life Sci. 2006 Mar 27;78(18):2088-98. PubMed.