A Dominant Mutation in a Neuronal Acetylcholine Receptor Subunit Leads to Motor Neuron Degeneration in Caenorhabditis elegans

Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2010; 30(42):13932-42. DOI: 10.1523/JNEUROSCI.1515-10.2010
Source: PubMed


Inappropriate or excessive activation of ionotropic receptors can have dramatic consequences for neuronal function and, in many instances, leads to cell death. In Caenorhabditis elegans, nicotinic acetylcholine receptor (nAChR) subunits are highly expressed in a neural circuit that controls movement. Here, we show that heteromeric nAChRs containing the acr-2 subunit are diffusely localized in the processes of excitatory motor neurons and act to modulate motor neuron activity. Excessive signaling through these receptors leads to cell-autonomous degeneration of cholinergic motor neurons and paralysis. C. elegans double mutants lacking calreticulin and calnexin-two genes previously implicated in the cellular events leading to necrotic-like cell death (Xu et al. 2001)-are resistant to nAChR-mediated toxicity and possess normal numbers of motor neuron cell bodies. Nonetheless, excess nAChR activation leads to progressive destabilization of the motor neuron processes and, ultimately, paralysis in these animals. Our results provide new evidence that chronic activation of ionotropic receptors can have devastating degenerative effects in neurons and reveal that ion channel-mediated toxicity may have distinct consequences in neuronal cell bodies and processes.

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Available from: Jason R Climer, Aug 25, 2014
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    • "In C. elegans, ACh is the major excitatory neurotransmitter, which directly or indirectly regulates locomotion (crawling and swimming) (Mullen et al., 2007), egg laying (Bany et al., 2003), pharyngeal pumping (McKay et al., 2004), defecation cycling (Thomas, 1990), and male mating (Liu and Sternberg, 1995). Gain-offunction nicotinic ACh receptor acr-2 (Barbagallo et al., 2010) and selenium (Se) (Estevez et al., 2012) are both able to induce cholinergic motor neuron degeneration and paralysis in worms. Another neurotransmitter, serotonin (5-HT), is synthesized in eight types of neurons and regulates locomotion, defecation, egg laying, male mating and pharyngeal pumping in worms (Mendel et al., 1995; Segalat et al., 1995; Weinshenker et al., 1995; Niacaris and Avery, 2003). "
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    ABSTRACT: The model species, Caenorhabditis elegans, has been used as a tool to probe for mechanisms underlying numerous neurodegenerative diseases. This use has been exploited to study neurodegeneration induced by metals. The allure of the nematode comes from the ease of genetic manipulation, the ability to fluorescently label neuronal subtypes, and the relative simplicity of the nervous system. Notably, C. elegans have approximately 60-80% of human genes and contain genes involved in metal homeostasis and transport, allowing for the study of metal-induced degeneration in the nematode. This review discusses methods to assess degeneration as well as outlines techniques for genetic manipulation and presents a comprehensive survey of the existing literature on metal-induced degeneration studies in the worm.
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    • "In addition to cognitive function, physical activity is also associated with ACh release (Dudar et al., 1979). As ACh receptors regulate the balance of muscle excitation and inhibition (Jospin et al., 2009; Barbagallo et al., 2010), and ACh impacts stamina and action potential of muscles (Lund et al., 2010), ACh receptor mutations lead to motor neuron degeneration. Indeed, ageing reduces ACh release and diminishes motor performance (Freeman and Gibson, 1988). "
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    • "ritic MT polarity are critical for localization of dendritic pro - teins , we analyzed the distribution of several dendritically targeted proteins . An acetylcholine receptor ( ACR - 2 ) , a receptor tyrosine kinase ( CAM - 1 ) , and a gap junction protein ( FBN - 1 ) are all reported to be dendritically enriched in DA9 ( Sieburth et al . , 2005 ; Barbagallo et al . , 2010 ) ."
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