Abstract
The transcription factor foxo is a known regulator of lifespan extension and tissue homeostasis. It has been linked to the maintenance of neuronal processes across many species and has been shown to promote youthful characteristics by regulating cytoskeletal flexibility and synaptic plasticity at the neuromuscular junction (NMJ). However, the role of foxo in aging neuromuscular junction function has yet to be determined. We profiled adult Drosophila foxo- null mutant abdominal ventral longitudinal muscles and found that young mutants exhibited morphological profiles similar to those of aged wild-type flies, such as larger bouton areas and shorter terminal branches. We also observed changes to the axonal cytoskeleton and an accumulation of late endosomes in foxo null mutants and motor neuron-specific foxo knockdown flies, similar to those of aged wild-types. Motor neuron-specific overexpression of foxo can delay age-dependent changes to NMJ morphology, suggesting foxo is responsible for maintaining NMJ integrity during aging. Through genetic screening, we identify several downstream factors mediated through foxo-regulated NMJ homeostasis, including genes involved in the MAPK pathway. Interestingly, the phosphorylation of p38 was increased in the motor neuron-specific foxo knockdown flies, suggesting foxo acts as a suppressor of p38/MAPK activation. Our work reveals that foxo is a key regulator for NMJ homeostasis, and it may maintain NMJ integrity by repressing MAPK signaling.
Highlights
Aging involves the progressive functional decline of cellular mechanisms and tissue integrity (Rose, 1994; Partridge and Barton, 1996; Lopez-Otin et al, 2013)
We found the 25-day adult flies had more than 2-fold more Rab7 punctae per regions of interest (ROIs) associated with the axon branch than the 1-week adults, demonstrating there is an increase in the number of late endosomes during aging (Figures 2D,E)
Foxo is known to act a regulator of synaptic plasticity and microtubule stability (Howlett et al, 2008; Nechipurenko and Broihier, 2012)
Summary
Aging involves the progressive functional decline of cellular mechanisms and tissue integrity (Rose, 1994; Partridge and Barton, 1996; Lopez-Otin et al, 2013). In the adult, this results in a gradual decline of synaptic contacts to skeletal muscle tissue, resulting in a loss of strength and muscle mass (Hall and Sanes, 1993). Synaptic plasticity, which allows for the maintenance of functional activity to protect against degeneration, can decline during aging, resulting in decreased neuronal responsiveness and synaptic deterioration (Bergado and Almaguer, 2002; Kempsell and Fieber, 2015; Wagner et al, 2015)
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