Figure 2. Neurodegenerative diseases in the PI 3-K/Akt/mTOR axis.

Phosphoinositide 3 kinase (PI 3-K)/Akt mediated mTOR activity is involved in pathogenesis of neurodegenerative diseases. Inhibition of mTOR by rapamycin can lead to autophagy under some conditions in neurodegenerative disorders. Autophagy may promote the clearance of aggregate prone proteins, such as huntingtin, α-synuclein, and beta-amyloid (Aβ) that contribute to the development of Huntington’s disease (HD), Parkinson’s disease (PD), and Alzheimer’s disease (AD) respectively. Activation of the downstream target of mTOR, p70 ribosome S6 kinase (p70S6K), through phosphorylation (p) prevents the induction of apoptosis and limits Aβ toxicity and ischemic neuronal injury. Yet, activation of p70S6K can promote the phosphorylation of Tau protein possibly contributing to neurofibrillary tangles. Neuronal atrophy in AD has been attributed to the insufficiency of retinoblastoma tumor suppressor (RB1) inducible Coiled-Coil 1 (RB1CC1), which functions to activate mTOR. Activation of mTOR prevents neurodegeneration of dopaminergic neurons during oxidative stress in models of PD. The stress response protein REDD1 expressed during PD inhibits the activation of mTOR. In some scenarios, activation of mTOR may also lead to dyskinesias. Inhibition of mTOR signaling through rapamycin may reduce the occurrence of epilepsy and improve functional recovery following traumatic brain injury (TBI).