Autophagosome formation is regulated by many signals that fall into two broad categories: mammalian target of rapamycin (mTOR)-dependent and mTOR-independent. The mTOR is a “classical” autophagy suppressor that acts by blocking the activity of the ULK1 complex. The activity of mTOR depends on various inputs from upstream signals that include the energy status and nutrient status of the cell, as well as the presence of amino acids and growth factors. Downstream of mTOR, numerous proteins encoded by
ATg genes are essential for the execution of autophagy.
12 Pathways that act independently of mTOR include 5′-AMP-activated protein kinase (AMPK), the stress-activated enzyme Jun N-terminal kinase 1 (JNK1), BH3-only proteins, the inositol 1,4,5-trisphosphate receptor (IP3R), Erk1/2, and calcium.
13−
15 Autophagy can also be pharmacologically induced by inhibiting negative regulators such as mTOR via the compound rapamycin
16 or by mTOR-independent inducers of autophagy such as trehalose.
17 Pharmacological inhibitors of autophagy include 3-methyladenine (3-MA), wortmannin, and LY294002.
18,
19
A number of enzymes have been proposed as potential targets of lithium action, including inositol monophosphatase (IMPase), a family of structurally related phosphomonoesterases, and the protein kinase glycogen synthase kinase-3.
20 Carmichael et al. found that the mood stabilizer lithium at 2.5–5 mM for 3 days (2–5 times human therapeutic plasma levels) reduced mutant huntingtin nuclear inclusions and apoptotic nuclear fragmentation in COS-7 African green monkey kidney cells and SKNSH human neuroblastoma cell lines transfected with mutant HTT exon 1 fragment possessing 74 CAG repeats.
21 Lithium’s autophagy-inducing property was first described by Sarkar et al. to enhance the clearance of aggregate-prone proteins, such as mutant forms of huntingtion and α-synuclein.
2 Lithium 10 mM was added to CoS-7, PC12, and mouse embryonic fibroblast cells transfected mutant HTT exon 1 with 74 CAG repeats.
2,
22,
23 GSK3β inhibition by lithium reduced autophagy by activating the mTOR.
23 On the other hand, lithium induced autophagy independently of mTOR through the inhibition of inositol monophosphatase (IMPase).
20,
22 IMPase catalyzes the hydrolysis of inositol monophosphate (IP1) into free inositol required for the phosphoinositol signaling pathway.
24 Lithium affects this pathway by inhibiting IMPase, leading to free inositol depletion, which in turn decreases myo-inositol-1,4,5-trisphosphate (IP3) levels (Figure
(Figure2).2). Increased inositol or IP3 levels inhibit autophagy, which reverse lithium’s effect.
2 IP3 and the stimulation of its receptor have been seen to suppress autophagy.
14 Inositol depletion is a common mechanism of mood-stabilizing drugs such as lithium, carbamazepine (CBZ) and valproic acid (VPA).
25 Consistent with the role of inositol depletion in autophagy regulation, CBZ and VPA also enhanced the clearance of aggregate-prone proteins.
2 The mTOR inhibitor rapamycin in combination with lithium is more protective than treatment with either compound alone in a Huntington’s disease model fly.23 This combination enhances autophagy by mTOR-independent (IMPase inhibition by lithium) and mTOR-dependent (mTOR inhibition by rapamycin) pathways. This treatment showed greater protection against neurodegeneration in an HD fly model with mTOR inhibition and lithium than either pathway alone.
