Ravi Allada, PhD
Edward C. Stuntz Distinguished Professor
Chair, Department of Neurobiology
Northwestern University
(April 25, 2017)
Circadian Clocks: From Fruit Flies to Fly Balls
Conditions such as Alzheimer’s or Huntington’s disease are associated with the accumulation of proteins that destroy certain nerve cells. The death of these neurons leads to the symptoms experienced by patients, such as movement problems in Huntington’s disease. More and more evidence is suggesting that circadian clocks may be disrupted early in the disease. Circadian clocks set the daily rhythm of processes in the body. Dr. Allada and his lab have used the fruit fly as a model for Huntington’s disease. Their research has determined that a protein associated with Huntington’s disease (mHtt) impairs circadian rhythms before symptoms appear. Altering the circadian clocks changed the rate of neuron death, due to mHtt. Dr. Allada’s future work will attempt to find the cellular pathways that link mHtt and circadian clocks.
Neurodegenerative diseases, such as Alzheimer’s and Huntington’s, commonly involve the accumulation and aggregation of neurotoxic proteins that impair and ultimately destroy specific neurons. Identifying processes that can slow neurodegeneration, especially before irreversible cell death, is a major challenge for the development of effective therapeutics. Accumulating evidence suggests that disrupted clocks are associated with, and even potentially alter, neurodegeneration at this early stage. To address the mechanistic relationship between circadian clocks and neurodegenerative diseases, we are using Huntington’s disease (HD) as a model. HD is caused by a triplet repeat expansion resulting in an expansion of a polyglutamine repeat in the Huntington protein (mHtt). Accumulation of mHtt results in degeneration of striatal, as well as cortical neurons, resulting in the characteristic motor and cognitive symptoms, and ultimately death. Considerable evidence from human and animal studies indicates that mHtt impairs circadian rhythms often before characteristic motor symptoms are even evident. In fact, master circadian pacemaker neurons are lost in HD patients. Yet little is known about the molecular mechanisms by which mHtt impairs circadian rhythmicity. In addition, it is unknown if circadian clocks, in turn, can modulate HD pathogenesis. To study the interplay between clocks and HD, the fruit fly Drosophila, a well-established model organism in the study of neurodegenerative disease and circadian clocks, has been employed. Both environmental and genetic perturbations of the circadian clock were shown to alter mHtt-mediated neurodegeneration, revealing that circadian clocks are not only a target of mHtt but may also be an important player in mediating mHtt-mediated pathogenesis. To identify potential genetic pathways that mediate the effect of the clock on mHtt, a novel behavioral platform has been developed for screening HD modifiers that would allow the identification of those genes that can modify pre-degenerative/functional and/or cell death effects of mHtt. As part of this screen, several novel pathways that mediate mHtt effects on behavior have been discovered, most notably the RNA binding protein Ataxin2. In addition, the molecular mechanisms by which novel modifiers function were explored in terms of mHtt inclusions, molecular clocks, and cell death, revealing effects on pre-degenerative neuronal dysfunction, as well as cell death. These studies exploit the advantages of the Drosophila system including the deep conservation with vertebrate models of circadian clocks and mechanisms of mHtt pathogenicity. High throughput fly genetics will be applied to reveal the elusive molecular and cellular pathways that bi-directionally link mHtt to clock disruption, a relatively understudied area of HD pathology and thus one ripe for the discovery of novel mechanisms.