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

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. In the nematode Caenorhabditis elegans, age-dependent morphological changes are widespread in somatic tissues (2-4). However, there is little evidence for neuronal aging in C. elegans (3). The observations by Herndon et al. (3) suggest that neuronal loss or axon guidance defects do not occur in the aging C. elegans nervous system. It was also shown that whereas nuclear membranes of other somatic cell nuclei undergo drastic age-dependent deterioration, those of neuronal nuclei remain relatively intact in aging animals (4).There is, however, a clear age-dependent behavioral decline in C. elegans, including decrease in pharyngeal pumping, locomotion and chemotaxis (5). Evidence suggests that failure in neuronal activity could play a direct role in age-dependent behavioral deterioration. Cai and Sesti (6) showed that age-dependent oxidation of the C. elegans potassium channel KVS-1 causes sensory loss and that protection of neuronal KVS-1 from oxidation rescues agedependent decline in chemotaxis behavior. Electrical activity has been shown to be important for neuronal development (7) and was recently implicated in the survival or maintenance of adult mammalian and Drosophila neurons (8, 9). However, it is unclear how electrical activity promotes the integrity of adult neurons.In this paper, we address whether more subtle, subcellular changes occur in the aging C. elegans nervous system. Our results indicate that C. elegans neurons do develop age-dependent changes. Moreover, we show that electrical activity and normal attachment to the neighboring epithelial cells are required for the maintenance of adult touch receptor neurons.

Guanine Nucleotide Exchange Factor OSG-1 Confers Functional Aging via Dysregulated Rho Signaling in Caenorhabditis elegans Neurons

“…We conclude that OSG-1 does not contribute to the regulation of life span in C. elegans. The nervous system of C. elegans undergoes several agedependent morphological and functional changes including cytoskeletal disorganization, axon beading, defasciculation, deteriorations in synaptic transmission, and neurite branching (Pan et al 2011;Tank et al 2011;Toth et al 2012;Liu et al 2013), and the results of this study add new insight by implicating Rho signaling in neuronal aging. In particular, the actin cytoskeleton appears to be one of the targets of OSG-1/RHO-1 as evidenced by the fact that knockdown of ARX-3 and ARX-5 alone or with RHO-1 or with OSG-1 ameliorated the loss of GFP signal in the ASER neuron in a nonadditive fashion.…”

AFF-1 fusogen can rejuvenate the regenerative potential of adult dendritic trees via self-fusion

“…Recently, aging-associated axonal morphological alterations and decline in regenerative capacity were described in C. elegans. daf-2 mutations delayed these age-related morphological changes and improved regeneration of aged severed axons in a daf-16-dependent manner (Byrne et al, 2014;Pan et al, 2011;Tank et al, 2011;Toth et al, 2012). Moreover, in the case of GABA motor neurons, as adult animals age there is a reduction in axon growth, retraction and regrowth in response to injury.…”

Alternative Perspectives on Aging inCaenorhabditis elegans: Reactive Oxygen Species or Hyperfunction?

“…It was recently discovered that aging neurons often sprout additional neurite branches (41,48) (Fig. 3).…”