MECHANISMS OF DEGENERATIVE CELL DEATH IN C ELEGANS

  • Driscoll, Monica (PI)
  • DRISCOLL, MONICA (PI)
  • DRISCOLL, MONICA A. (PI)
  • DRISCOLL, MONICA (PI)
  • DRISCOLL, MONICA (PI)

Project Details

Description

Inherited neurodegenerative conditions have been identified in organisms
as diverse as nematodes and man, but relatively little is understood about
the genes involved and the mechanisms whereby mutant alleles induce
inappropriate cell death. We study members of a family of genes, called
degenerins, which can mutate to induce late onset swelling and necrotic-
like death of specific groups of neurons in the easily studied nematode
Caenorhabditis elegans. The degenerin gene family was originally defined
by unusual dominant "killer" alleles of the mec4 and deg-I genes. Three
degenerin-related genes from the rat, alpha-, beta-, and gamma rENaC, have
been demonstrated to encode subunits of the amiloride-sensitive epithelial
Na+ channel. We have speculated that the C. elegans degenerins mec-4 and
mec-10 encode components of a mechanosensory ion channel, an exciting
working hypothesis because eukaryotic mechanosensory channel components
have not previously been isolated and the molecular properties of these
channels are unknown. Our experiments indicate that ineffective channel
closing is the critical event in the initiation of neurodegeneration.

My long term research plan is to decipher in molecular detail how
misregulation of ion channel activity (and other insults) induce necrotic-
like death and to define the molecular events that transpire during
neurodegeneration. Experiments outlined in this proposal are designed to
enable us to describe how degeneration is initiated, what proteins are
needed to enact the death, and even how cell corpses are removed. In
addition, we will define distinctions/common features between degenerative
cell death and the programmed cell death pathway (which we now believe
overlap more than we originally anticipated). Finally, we expect to
exploit the ability of mec4(d) to act as a killer gene to create ablation
vectors and to set up a model system for studying degenerin-induced death
in mammalian cell culture. Specifically, we will: l) assay the activities
of wild-type and mutant channels in a oocyte expression system, 2) conduct
genetic suppressor screens to identify genes essential for mec4(d)-induced
neurodegeneration, 3) define effects of programmed cell death genes on
touch cell degeneration, and 4) determine whether mec4(d) and potentially
lethal variants of degenerin-related genes can induce degeneration in
heterologous systems, develop ablation vectors which depend on the
toxicity of these genes, and set up a mammalian culture model for
degenerin-induced death.

The proposed work is important to heath related issues in that it will
advance understanding of degenerative cell death mechanisms and may
inspire novel strategies for the prevention of injury-induced cell death.
In addition, these studies will contribute to the characterization of a
new ion channel class with a likely function in mechanotransduction a
phenomenon which contributes to senses of touch, hearing and balance and
more.
StatusFinished
Effective start/end date8/1/951/31/14

Funding

  • National Institute of Neurological Disorders and Stroke: $274,133.00
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke: $7,725.00
  • National Institute of Neurological Disorders and Stroke: $63,183.00
  • National Institute of Neurological Disorders and Stroke: $330,562.00
  • National Institute of Neurological Disorders and Stroke: $334,157.00
  • National Institute of Neurological Disorders and Stroke: $316,910.00
  • National Institute of Neurological Disorders and Stroke: $326,954.00

ASJC

  • Medicine(all)
  • Neuroscience(all)
  • Clinical Neurology
  • Neurology
  • Genetics
  • Biochemistry, Genetics and Molecular Biology(all)
  • Molecular Biology
  • Cell Biology

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