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2013 Scientific Report

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VARI | 2013 Research Interests As the average human life span continues to rise, the likelihood of an individual developing a neurodegenerative disease also increases. Thus, there is an increasing need to understand the aging process and its role in the development of age-onset disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Research in this laboratory is focused on gaining insight into the aging process and the pathogenesis of such diseases. In addition to the obvious benefit to the individual, this work has the potential to be a great benefit to society by decreasing health care costs and helping to maintain productivity and independence to a later age. Oxidative stress and longevity The widely accepted free radical theory of aging (FRTA) proposes that aging results from the accumulation of oxidative damage caused by reactive oxygen species (ROS) generated during normal metabolism. Recent work in the worm Caenorhabditis elegans has indicated that the relationship between ROS and life span is more complex than anticipated. Decreasing the antioxidant defense through the deletion of individual, or combinations of, superoxide dismutase (SOD) genes does not decrease life span. This is contrary to expectations, because SOD is an enzyme that decreases the levels of ROS. In fact, quintuplemutant worms lacking all five sod genes live as long as wild-type worms, despite a markedly increased sensitivity to oxidative stress. Thus, it appears that while oxidative damage increases with age, it does not cause aging. Recent evidence suggests that increased levels of superoxide can act as a pro-survival signal that leads to increased longevity. This is demonstrated by the fact that either deletion of the mitochondrial superoxide dismutase gene sod-2 or treatment of wild-type worms with the superoxide generator paraquat results in increased life span. The fact that sod quintuple-mutant worms exhibit a normal life span despite markedly increased sensitivity to oxidative stress suggests a balance between superoxide-mediated pro-survival signaling and the toxic effects of superoxide. Thus, one of the main goals of this work is to elucidate the mechanism by which superoxide-mediated pro-survival signaling leads to increased longevity: how increased levels of superoxide trigger the signal, how the signal is transmitted, and what changes that the signal introduces lead to increased life span. These experiments use a combination of genetic mutants and RNA interference to gain insight into the signaling mechanism. The role of aging in neurodegenerative disease Advancing age is the greatest risk factor for the development of neurodegenerative disease. In the familial forms of these diseases, the mutation that causes the disease is present from birth, and yet the symptoms do not appear for several decades. This suggests that changes during normal aging may make cells more susceptible to the disease-causing mutations. This is supported by the fact that the onset of these disorders in animal models is proportional to the life span of the organism, indicating disease progression according to biological age and not chronological time. In fact, multiple changes are known to occur during normal aging that likely reduce the ability of cells to protect themselves against the effects of toxic diseasecausing proteins. In support of this concept, interventions that are known to extend life span, such as caloric restriction, have shown benefit in both worm and mouse models of Huntington’s disease. Thus, by gaining insight into the aging process and examining its role in the pathogenesis of neurodegenerative disease, it may be possible to develop treatments for these devastating disorders. 55

Van Andel Research Institute | Scientific Report Huntington’s disease (HD) is an adult-onset neurodegenerative disorder characterized by motor dysfunction, cognitive deficits, and neuropsychiatric abnormalities. Disease onset typically occurs between the ages of 35 and 55 and progresses inevitably to death approximately 15 years later. The disease is caused by a trinucleotide CAG repeat expansion in the HD gene, which codes for the protein huntingtin (HTT). The CAG repeat sequence is translated into a polyglutamine tract in the HTT protein, and thus HD belongs to a group of at least nine polyglutamine toxicity disorders. Interestingly, while the size of the CAG repeat is polymorphic in unaffected individuals (ranging from 9 to 35 repeats), the disease range begins at precisely 35 CAG repeats, and the severity of the disease is correlated with the length of the repeat. Both worms and mouse models of HD have been created through transgenic expression of varying lengths of the huntingtin protein with a disease-length polyglutamine tract. The worm models express the mutant polyglutamine sequence either in body wall muscle or in neurons. These worms exhibit numerous abnormal phenotypes—including decreased life span, slow development, and decreased mobility—that are not observed in worms expressing a normal length repeat. Mouse models of HD have been shown to recapitulate almost all features of human HD, including motor deficits, cognitive deficits, and selective neurodegeneration. Our project examines 1) whether genes that increase life span will be beneficial in worm models of HD (i.e., will the increased longevity imparted by the aging gene reduce the severity of the polyglutamine toxicity phenotypes?), and 2) whether specific changes that take place during normal aging and that have been implicated in neurodegenerative disease contribute to pathogenesis in worm models of HD (i.e., do the higher levels of oxidative stress in older individuals contribute to pathogenesis?). Both of these objectives are being studied using two complementary approaches: genetic crosses to generate double mutants, and specific knockdown of gene expression using RNAi. The results from the worm screen will be used to prioritize the genes that will be studied in mouse models, which provide more physiologically accurate models of HD. Similar experiments are being conducted in animal models of Parkinson’s disease. By comparing the results, it will be possible to identify both overlapping and disease-specific mechanisms in these two neurodegenerative disorders. 56

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