Cell type specific neurodegeneration has been identified in invertebrate and vertebrate animals across Phyla. Yet the molecular mechanisms underlying postdevelopmental neuron cell death are poorly understood. Clues from genetic model organisms are rapidly narrowing the gap in our understanding of neurodegeneration. We have identified and are characterizing a mutation that causes degeneration of the C. elegans sensory ASH neurons. Several characteristics of the ASH neuron make it particularly amenable to the study of neurodegeneration. Survival and morphology of the ASH neuron are easily observed in vivo . The sensory ending of the ASH neuron directly contacts the environment. When the ciliated sensory ending of the ASH neuron is morphologically intact, the neuron can take up fluorescent lipophilic dyes including DiD, allowing direct visualization of the neuron. Survival of the ASH neuron is assessed by detection of green fluorescent protein (GFP) driven by an ASH neuron specific promoter. A neuron that fails to take up DiD, but expresses GFP has degenerated, but has not died. This system provides a visible phenotype for identification of changes involved in neuronal integrity and survival. A recessive, cold sensitive mutation was isolated in a genetic screen for ASH neuron specific degeneration. 90% of the ASH neurons are lost by adulthood in
rt70 mutant animals that are raised at 15 o C. However, if
rt70 mutant animals are raised at 27 o C, ASH neurons survive and are morphologically normal. In addition to ASH neurons, at least one class of neurons in the anterior ganglion and one class of ventral nerve cord neurons are affected in
rt70 mutant animals. In contrast to phenotypes associated with apoptotic death, neurons in
rt70 mutant animals swell and vacuolate prior to death. This degeneration phenotype suggests misregulation of osmotic balance. Four gain of function alleles that cause similar neurodegeneration in C. elegans encode ion channels (CGC# 2167, 1299, 2711, 1871). Interestingly,
rt70 maps to a 700 kb region on the X chromosome that contains seven putative ion channels. Currently, single nucleotide polymorphisms are being used to map
rt70 more precisely. Cosmids within the region will be injected to identify the
rt70 mutation. A molecular, genetic, and functional analysis of
rt70 will provide important information about degeneration of specific sets of neurons.