The FoxO Transcription Factors, Autophagy and mTOR
The set of forkhead box (FoxO) transcription factors play an essential role in neurodevelopment. FoxO3 enters the nucleus and activates the gene expression of a set of proteins involved in diverse cellular processes, including proliferation and autophagy [221,222]. Conditional deletion of FoxO1, FoxO3 and FoxO4 strongly impairs autophagy in developing neurons in the hippocampus [223]. Furthermore, FoxO deficiency leads to altered dendritic morphology and increased spine density in mouse hippocampal neurons [223].
The PI3K/Akt/mTOR pathway involves complex feedback loops that regulate the balance between anabolic and catabolic activities via two critical branches, mTORC1 and mTORC2. mTOR signaling is disrupted in association with autism [224]. Both the FoxO transcription factors and mTORC1 are downstream effectors of Akt. FoxO expression suppresses mTORC1 and increases activation of the PI3K/Akt/mTORC2 pathway [225]. Insufficient FoxO expression leads to impaired autophagy, while at the same time promoting proliferation and differentiation through increased activation of mTORC1. Impaired autophagy is a common feature found in association with autism [226]. Autophagy is essential for synaptic pruning, which is impaired in autism [115].
PIN1 plays an essential role in facilitating the translocation of FoxO3 to the nucleus to effect activation of its target proteins [227]. Thus, PIN1 deficiency leads to impaired autophagy due to inactivation of FoxO3. The mTORC1 pathway activates the transcription factor NRF2, while at the same time inhibiting autophagy [228].
The degradation and clearance of damaged molecules in a cell are achieved mainly through macroautophagy and the ubiquitin proteasome [229]. mTORC1 is a well-established inhibitor of macroautophagy. It not only inhibits the induction of autophagy by phosphorylating the core proteins involved in initiation, but also targets each subsequent step of the autophagy process [230].
The rates of hearing loss, both moderate and severe, among autistic children are much higher than the rates in the general population [231]. Overactive mTORC1 in the cochlea is one of the critical causes of age-related hearing loss [232]. Studies on mice revealed that Rapamycin, a potent inhibitor of mTORC1 [233], along with N-acetylcysteine supplementation, could rescue cochlear hair cells from injury due to oxidative stress. PIN1 protects hair cells from senescence by inhibiting the PI3K/Akt/mTOR pathway [234]. Juglone is a drug that is known to reduce expression of PIN1. Treatment of mice with hydrogen peroxide and juglone induced ROS-related phosphorylation of p53. This resulted in damage to the cochlea and hearing loss due to cellular senescence [234].
Altered dopamine signaling has been implicated as a contributing factor in autism, and this could be due to impaired autophagy [235]. Chronic lack of autophagy enhances evoked dopamine release from dopaminergic neurons [236].