FoxO Proteins in the Nervous System

Table 1

Forkhead box class O (FoxO) in the nervous system.

Pathway	Function
Tissue expression	FoxO proteins are expressed in all tissues of the body; FoxO proteins appear to have selective expression in the nervous system that may offer insight into the biology of specific FoxO proteins; FoxO proteins may be applicable for multiple neurodegenerative disorders that include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and auditory neuronal disease
Epigenetic and posttranslational modification	FoxO proteins are controlled by posttranslation protein modifications that involve phosphorylation, acetylation, and ubiquitylation that involve Akt, SgK, MST1, IKK, SIRT1, and Wnt signaling with WISP1
Oxidative stress	FoxO proteins may be required for oxidative stress to result in apoptosis and can disrupt proliferative pathways of Wnt signaling; FoxO proteins have been linked to disease progression and oxidative stress can modify FoxO interactions with other proteins that can ultimately influence cell neuronal survival
Autophagy and apoptosis	During oxidative stress, FoxO proteins can lead to the induction of autophagy and promote cell survival to clear the presence of toxic proteins such as mHtt, α-synuclein, and Aβ; Under some circumstances with autophagy, a reduction in autophagy is required for protection indicating that FoxO cytoprotection may not always be directly tied to the induction of autophagy; Protection against apoptosis usually requires inhibition or gene knockdown of FoxO proteins to protect against injuries such as cerebral ischemia, microglial and inflammatory cell demise, and Aβ exposure. Protection with metabotropic glutamate receptors, NAD^+ precursors, and trophic factors such as EPO requires inhibition and nuclear export of FoxO proteins
Stem cells	Activity of FoxO proteins can be necessary for the development of hematopoietic stem cells, dopaminergic cells, muscle regeneration, and oligodendrocyte progenitor development and myelination; At times, reduction in FoxO protein activity is required for cell development and differentiation such as with pancreatic beta cell survival, osteoblast precursors, embryonic stem cells, and enteric nervous system precursors

Akt: protein kinase B; Aβ: beta-amyloid; EPO: erythropoietin; IKK: IκB kinase; MST1: mammalian sterile 20-like kinase-1; mHtt: mutant Huntingtin; SgK: NAD⁺: nicotinamide adenine dinucleotide; serum- and glucocorticoid-inducible protein kinase; SIRT1: silent mating type information regulation 2 homolog 1 (S. cerevisiae); WISP1: wnt1 inducible signaling pathway protein 1.