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].