C. elegansmodel of neuronal aging

Abstract

Aging of the nervous system underlies the behavioral and cognitive decline associated with senescence. Understanding the molecular and cellular basis of neuronal aging will therefore contribute to the development of effective treatments for aging and age-associated neurodegenerative disorders. Despite this pressing need, there are surprisingly few animal models that aim at recapitulating neuronal aging in a physiological context. We recently developed a C. elegans model of neuronal aging, and showed that age-dependent neuronal defects are regulated by insulin signaling. We identified electrical activity and epithelial attachment as two critical factors in the maintenance of structural integrity of C. elegans touch receptor neurons. These findings open a new avenue for elucidating the molecular mechanisms that maintain neuronal structures during the course of aging.

A C. elegans model for neurodegeneration in Cockayne syndrome

“…The progressive loss of neuronal integrity in csb-1 mutants was characterized by an early-onset of increased beading that precedes axonal degeneration. We also detected aberrant neurite morphology, bubble-like lesions (bridging) and neurite sprouting (branching) along the axons of mechanosensory neurons; features that naturally appear during advanced age in the C. elegans neuronal system ( 20 ). Neuronal maintenance in ageing is governed by the Jun kinase (JNK-1) and insulin signalling via DAF-16/FOXO ( 20 , 46 , 47 ), both of which have been implicated in the DNA damage response (DDR; ( 15 , 48 ).…”

“…We also detected aberrant neurite morphology, bubble-like lesions (bridging) and neurite sprouting (branching) along the axons of mechanosensory neurons; features that naturally appear during advanced age in the C. elegans neuronal system ( 20 ). Neuronal maintenance in ageing is governed by the Jun kinase (JNK-1) and insulin signalling via DAF-16/FOXO ( 20 , 46 , 47 ), both of which have been implicated in the DNA damage response (DDR; ( 15 , 48 ). We previously showed that the activation of the transcription factor DAF-16 upon UV-induced DNA damage promotes developmental growth and lifespan in csb-1 mutants thus counteracting the consequences of unrepaired DNA damage ( 13 , 15 ).…”

“…In order to examine why the sensitivity to gentle mechanosensory stimuli was lower in the csb-1 mutant strain, we questioned whether the animals were losing neuronal integrity. Using the double mutant zdls5[mec-4::GFP+lin-15(+)]I;csb-1(ok2335) , we scored for neuronal defects that previously have been characterised in an age-dependent analysis of neuronal decline ( 20 ). We identified a range of abnormalities, including axonal beading, axonal degeneration, axonal disorganization (zig-zag-like structures), axonal branching, protrusions emerging from the neuronal cell body, and bridging of axons ( Supplementary Figure S2A ).…”

“…Here, we demonstrate that csb-1 mutants exhibit progressive functional loss of sensory neuronal function that is exacerbated by UV irradiation or infliction of transcription-blocking DNA lesions by the fungal toxin Illudin M, emphasizing the causal role of DNA lesions in the pathology. We determine different types of progressive neuronal defects, with an accentuated level of beading (described as focal enlargements along the axonal process) in csb-1 mutant animals, a phenotype, which precedes neuronal degeneration ( 20 ). Consistent with a role of mitochondrial dysfunction in CS-related functional deterioration, we observe higher levels of mitochondrial mass and a disturbed mitochondrial network.…”

A microfluidic platform for lifelong high-resolution and high throughput imaging of subtle aging phenotypes inC. elegans

“…Several aspects involved in aging and longevity have been studied in this model organism, such as DNA damage, mitochondrial dysfunction, autophagy impairment, and nutrient sensing dysregulation 11,12 . Some efforts have also been devoted to explore neurodegeneration induced by aging, as C. elegans is also very important in neuroscience studies, mainly due to its fully mapped neuronal connections 11,13–18 . Aging induces phenotypes reminiscent of functional deterioration in the nervous system: motility decline, long-term associative memory deterioration, and changes in neuronal morphology and synaptic patterning 14,15,17–19 .…”