Diapause Formation and Downregulation of Insulin-Like Signaling via DAF-16/FOXO Delays Axonal Degeneration and Neuronal Loss

Abstract

Axonal degeneration is a key event in the pathogenesis of neurodegenerative conditions. We show here that mec-4d triggered axonal degeneration of Caenorhabditis elegans neurons and mammalian axons share mechanistical similarities, as both are rescued by inhibition of calcium increase, mitochondrial dysfunction, and NMNAT overexpression. We then explore whether reactive oxygen species (ROS) participate in axonal degeneration and neuronal demise. C. elegans dauers have enhanced anti-ROS systems, and dauer mec-4d worms are completely protected from axonal degeneration and neuronal loss. Mechanistically, downregulation of the Insulin/IGF-1-like signaling (IIS) pathway protects neurons from degenerating in a DAF-16/FOXO–dependent manner and is related to superoxide dismutase and catalase-increased expression. Caloric restriction and systemic antioxidant treatment, which decrease oxidative damage, protect C. elegans axons from mec-4d-mediated degeneration and delay Wallerian degeneration in mice. In summary, we show that the IIS pathway is essential in maintaining neuronal homeostasis under pro-degenerative stimuli and identify ROS as a key intermediate of neuronal degeneration in vivo. Since axonal degeneration represents an early pathological event in neurodegeneration, our work identifies potential targets for therapeutic intervention in several conditions characterized by axonal loss and functional impairment.

FOXO protects against age‐progressive axonal degeneration

“…These results corroborate that FOXO confers and supports physiological health measures via neuroprotection. Together, these results demonstrate that the loss of FOXO accelerates axonal degeneration and ultimately leads to motor dysfunction, a finding consistent with previous study in C. elegans (Calixto, Jara & Court, 2012). …”

Age- and manganese-dependent modulation of dopaminergic phenotypes in a C. elegans DJ-1 genetic model of Parkinson's disease

“…DAF-16 is the C. elegans orthologue of human FOXO, and it functions as a transcription factor responsible for antioxidant response. daf-16 deletion has been shown to greatly reduce lifespan and stress tolerance 42, 44, 45, 62 . Here we show that overexpression of DAF-16::GFP fully reversed lifespan reduction caused by djr-1.2 deletion and Mn exposure (Fig.…”

“…Worms enter dauer stage after L2 as an alternative to L3 when conditions for reproduction are poor, either because of lack of food or presence of a chemical or physical stressor (i.e. high or low temperature) 41, 42 .…”

“…One of the important regulators of lifespan, abnormal dauer formation 16 (DAF-16)/forkhead box O (FOXO), is also a transcriptional regulator of antioxidant response, suggesting aging coincides with oxidant management. Dauer stage entrance is also regulated by daf-16 and its upstream regulator daf-2 /InR (insulin receptor) 42-45 . Insulin signaling via daf-2 / daf-16 /FOXO pathway has been implicated in the control of a variety of downstream antioxidant genes responsible for antioxidant response including positive self regulation of daf-16 44, 46, 47 , and combined or individual regulation of hsp-16.2, sod-3, sod-1 and gst-4 43 , although the contribution of DAF-16 to lifespan and DAergic associated response to Mn has not been previously examined.…”

The Apoptotic Engulfment Machinery Regulates Axonal Degeneration in C. elegans Neurons

“…Although several studies have examined axonal degeneration in C. elegans in the context of neurodegenerative disease models and neuronal dysfunction (Calixto et al, 2012; Nagarajan et al, 2014; Neumann and Hilliard, 2014; Neumann et al, 2011), no Wallerian degeneration (i.e. severed axon) paradigm has been investigated.…”