Table 2. Beneficial effects of the chemical inducers of autophagy in models of lysosomal storage disorders.
Autophagy inducer | Mechanism of autophagy induction | LSD | Beneficial effects in LSD models |
---|---|---|---|
mTOR-DEPENDENT AUTOPHAGY INDUCER | |||
Rapamycin [42] | Inhibition of mTORC1 [42] | NPC1 | Rescue of autophagic flux and improvement in cell viability in mutant Npc1 MEFs [73], mouse neurons with Npc1 knockdown [73] and NPC1 patient iPSC-derived neuronal and hepatic cells [74] |
NPB | Reduction in mitochondrial ROS and lipid droplets, and induction of lysosomal exocytosis in NPB patient B lymphocytes [148] | ||
PD | Reduction in muscle glycogen in Gaa-deficient mice when treated together with recombinant human GAA [167]; Improved autophagic flux and GAA maturation in Pompe disease patient myotubes [117] | ||
GD | Improvement in lifespan and locomotor activity in GD Drosophila model [97] | ||
mTOR-INDEPENDENT AUTOPHAGY INDUCER | |||
Trehalose [44] | Inhibition of SLC2A glucose transporters [145]; Activation of TFEB by Akt inhibition [144] | NPC1 | Rescue of autophagic flux and improvement in cell viability in NPC1 patient iPSC-derived neurons [74] |
CLN3 | Clearance of ceroid lipopigment deposits in CLN3 patient fibroblasts, and attenuation of neuropathology and extension of lifespan in Cln3-deficient mice [144] | ||
Carbamazepine [35] | Reduction in inositol and IP3 levels [35] | NPC1 | Rescue of autophagic flux and improvement in cell viability in NPC1 patient iPSC-derived neurons and hepatic cells [74] |
Lithium [35] | Inhibition of IMPase and reduction in inositol and IP3 levels [35] | NPC1 | Rescue of autophagic flux in mutant Npc1 MEFs [73] |
CLN3 | Rescue of autophagic flux and improvement in cell viability in mutant Cln3 cerebellar cells [146] | ||
L-690,330 [35] | Inhibition of IMPase and reduction in inositol and IP3 levels [35] | CLN3 | Rescue of autophagic flux and improvement in cell viability in mutant Cln3 cerebellar cells [146] |
Verapamil [36] | Inhibition of L-type Ca2+ channel and reduction in cytosolic Ca2+ [36] | NPC1 | Rescue of autophagic flux and improvement in cell viability in NPC1 patient iPSC-derived neurons [74] |
BRD2716, BRD5631, BRD34009 [142] | Unknown | NPC1 | Rescue of autophagic flux and improvement in cell viability in NPC1 patient iPSC-derived neurons [142] |
Abbreviations: CLN, ceroid lipofuscinosis neuronal disease; GD, Gaucher disease; IMPase, inositol monophosphatase; IP3, inositol 1,4,5-trisphosphate; iPSC, induced pluripotent stem cells; LSD, lysosomal storage disorder; mTORC1, mechanistic target of rapamycin complex I; NPB, Niemann–Pick type B disease; NPC1, Niemann–Pick type C1 disease; PD, Pompe disease; SLC2A, Solute carrier 2A; TFEB, Transcription factor EB.