Genetic analysis of age-dependent defects of the Caenorhabditis elegans touch receptor neurons

Edited by Mu-ming Poo, University of California, Berkeley, California, and approved April 19, 2011 (received for review August 8, 2010)
May 12, 2011
108 (22) 9274-9279

Abstract

Although many genes have been implicated in the pathogenesis of common neurodegenerative diseases, the genetic and cellular mechanisms that maintain neuronal integrity during normal aging remain elusive. Here we show that Caenorhabditis elegans touch receptor and cholinergic neurons display age-dependent morphological defects, including cytoskeletal disorganization, axon beading, and defasciculation. Progression of neuronal aging is regulated by DAF-2 and DAF-16 signaling, which also modulate adult life span. Mutations that disrupt touch-evoked sensory activity or reduce membrane excitability trigger accelerated neuronal aging, indicating that electrical activity is critical for adult neuronal integrity. Disrupting touch neuron attachment to the epithelial cells induces distinct neurodegenerative phenotypes. These results provide a detailed description of the age-dependent morphological defects that occur in identified neurons of C. elegans, demonstrate that the age of onset of these defects is regulated by specific genes, and offer experimental evidence for the importance of normal levels of neural activity in delaying neuronal aging.

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Acknowledgments

We thank Cori Bargmann, Gian Garriga, Miriam Goodman, Barth Grant, Joshua Kaplan, Cynthia Kenyon, Bruce Vogel, June-Tai Wu, and the Caenorhabditis Genetics Center for providing some of the strains and reagents used in this study and Andre Ho and Yi-Chun Wu for assistance with microinjection. We thank Gian Garriga, Jason Chien, Matthew Schreiber, and Fred Wolf for critical reading and comments on the manuscript. This work was supported by National Science Council (Taiwan) Grant NSC 99-2320-B-002-080 (to C.-L.P.) and funding from the state of California for medical research on alcohol and substance abuse through the University of California at San Francisco (to S.M.).

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References

1
BA Yankner, T Lu, P Loerch, The aging brain. Annu Rev Pathol 3, 41–66 (2008).
2
D Garigan, et al., Genetic analysis of tissue aging in Caenorhabditis elegans: A role for heat-shock factor and bacterial proliferation. Genetics 161, 1101–1112 (2002).
3
LA Herndon, et al., Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans. Nature 419, 808–814 (2002).
4
E Haithcock, et al., Age-related changes of nuclear architecture in Caenorhabditis elegans. Proc Natl Acad Sci USA 102, 16690–16695 (2005).
5
JJ Collins, C Huang, S Hughes, K Kornfeld, The measurement and analysis of age-related changes in Caenorhabditis elegans. WormBook , Jan 24, 1–21 (2008).
6
SQ Cai, F Sesti, Oxidation of a potassium channel causes progressive sensory function loss during aging. Nat Neurosci 12, 611–617 (2009).
7
NC Spitzer, Electrical activity in early neuronal development. Nature 444, 707–712 (2006).
8
CW Lin, et al., Genetically increased cell-intrinsic excitability enhances neuronal integration into adult brain circuits. Neuron 65, 32–39 (2010).
9
A Chiang, R Priya, M Ramaswami, K Vijayraghavan, V Rodrigues, Neuronal activity and Wnt signaling act through Gsk3-beta to regulate axonal integrity in mature Drosophila olfactory sensory neurons. Development 136, 1273–1282 (2009).
10
M Chalfie, J Sulston, Developmental genetics of the mechanosensory neurons of Caenorhabditis elegans. Dev Biol 82, 358–370 (1981).
11
Z Wang, Y Jin, Genetic dissection of axon regeneration. Curr Opin Neurobiol 21, 189–196 (2011).
12
CJ Kenyon, The genetics of ageing. Nature 464, 504–512 (2010).
13
L Avery, The genetics of feeding in Caenorhabditis elegans. Genetics 133, 897–917 (1993).
14
AL Hsu, CT Murphy, C Kenyon, Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300, 1142–1145 (2003).
15
M Chalfie, Neurosensory mechanotransduction. Nat Rev Mol Cell Biol 10, 44–52 (2009).
16
M Chalfie, M Au, Genetic control of differentiation of the Caenorhabditis elegans touch receptor neurons. Science 243, 1027–1033 (1989).
17
DS Chelur, et al., The mechanosensory protein MEC-6 is a subunit of the C. elegans touch-cell degenerin channel. Nature 420, 669–673 (2002).
18
M Driscoll, M Chalfie, The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration. Nature 349, 588–593 (1991).
19
H Du, G Gu, CM William, M Chalfie, Extracellular proteins needed for C. elegans mechanosensation. Neuron 16, 183–194 (1996).
20
L Emtage, G Gu, E Hartwieg, M Chalfie, Extracellular proteins organize the mechanosensory channel complex in C. elegans touch receptor neurons. Neuron 44, 795–807 (2004).
21
BE Vogel, EM Hedgecock, Hemicentin, a conserved extracellular member of the immunoglobulin superfamily, organizes epithelial and other cell attachments into oriented line-shaped junctions. Development 128, 883–894 (2001).
22
JM Muriel, C Dong, H Hutter, BE Vogel, Fibulin-1C and fibulin-1D splice variants have distinct functions and assemble in a hemicentin-dependent manner. Development 132, 4223–4234 (2005).
23
ZW Wang, O Saifee, ML Nonet, L Salkoff, SLO-1 potassium channels control quantal content of neurotransmitter release at the C. elegans neuromuscular junction. Neuron 32, 867–881 (2001).
24
ER Troemel, A Sagasti, CI Bargmann, Lateral signaling mediated by axon contact and calcium entry regulates asymmetric odorant receptor expression in C. elegans. Cell 99, 387–398 (1999).
25
AG Davies, et al., A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans. Cell 115, 655–666 (2003).
26
SH Freeman, et al., Preservation of neuronal number despite age-related cortical brain atrophy in elderly subjects without Alzheimer disease. J Neuropathol Exp Neurol 67, 1205–1212 (2008).
27
DW Schultz, et al., Analysis of the ARMD1 locus: Evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family. Hum Mol Genet 12, 3315–3323 (2003).
28
A Bounoutas, R O'Hagan, M Chalfie, The multipurpose 15-protofilament microtubules in C. elegans have specific roles in mechanosensation. Curr Biol 19, 1362–1367 (2009).
29
N Kourtis, N Tavernarakis, Non-developmentally programmed cell death in Caenorhabditis elegans. Semin Cancer Biol 17, 122–133 (2007).

Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 108 | No. 22
May 31, 2011
PubMed: 21571636

Classifications

Submission history

Published online: May 12, 2011
Published in issue: May 31, 2011

Keywords

  1. extracellular matrix
  2. insulin signaling
  3. ion channels
  4. mechanosensory neurons
  5. neurodegeneration

Acknowledgments

We thank Cori Bargmann, Gian Garriga, Miriam Goodman, Barth Grant, Joshua Kaplan, Cynthia Kenyon, Bruce Vogel, June-Tai Wu, and the Caenorhabditis Genetics Center for providing some of the strains and reagents used in this study and Andre Ho and Yi-Chun Wu for assistance with microinjection. We thank Gian Garriga, Jason Chien, Matthew Schreiber, and Fred Wolf for critical reading and comments on the manuscript. This work was supported by National Science Council (Taiwan) Grant NSC 99-2320-B-002-080 (to C.-L.P.) and funding from the state of California for medical research on alcohol and substance abuse through the University of California at San Francisco (to S.M.).

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Chun-Liang Pan1 [email protected]
Ernest Gallo Clinic and Research Center and Department of Neurology, University of California, San Francisco, Emeryville, CA 94608;
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
Chiu-Ying Peng
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
Chun-Hao Chen
Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
Steven McIntire1 [email protected]
Ernest Gallo Clinic and Research Center and Department of Neurology, University of California, San Francisco, Emeryville, CA 94608;

Notes

1
To whom correspondence may be addressed. E-mail: [email protected] and [email protected].
Author contributions: C.-L.P. and S.M. designed research; C.-L.P., C.-Y.P., and C.-H.C. performed research; C.-L.P., C.-Y.P., C.-H.C., and S.M. analyzed data; and C.-L.P. and S.M. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Genetic analysis of age-dependent defects of the Caenorhabditis elegans touch receptor neurons
    Proceedings of the National Academy of Sciences
    • Vol. 108
    • No. 22
    • pp. 8917-9316

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