Table 1 Small molecule compounds targeting TDP-43, mitochondria, and autophagy
Target | Drug | Mechanism | Reference |
|---|---|---|---|
TDP-43 | Mitoxantrone | Reduces the recruitment of TDP-43 from SGs and prevents the formation of TDP-43 aggregates | [142] |
Trimethylamine N-oxide (TMAO) | Enhances TDP-43 LLPS but prevents protein fibrillation in vitro | [143] | |
rTRD01 | Prevents RNA or DNA from binding to TDP-43 to reduce neuronal toxicity | [144] | |
PF 670462 | Inhibits casein kinases 1 to reduce TDP-43 phosphorylation and aggregation | ||
D4476 | |||
Olomoucine | Inhibits cyclin-dependent kinase 2 (CDK2) to reduce TDP-43 accumulation in SGs | ||
SB 415286 | Inhibits glycogen synthase kinase 3β (GSK3β) to reduce TDP-43 accumulation in SGs | ||
IGS2.7 | Inhibits CK1 to reduce TDP-43 phosphorylation and restores nuclear protein localization to restore TDP-43 homeostasis | [149] | |
IGS3.27 | |||
Mitochondria | MitoQ | Mitochondria-targeting antioxidant | [150] |
AICAR | Activates AMPK, which then acts on PGC-1α | [151] | |
Nicotinamide mononucleotide (NMN) | Increases NAD+ pools and activates mitochondrial unfolded protein response | ||
Resveratrol | Activates SIRT1, which then acts on PGC-1α | ||
Rimonabant | Activates eNOS; increases mitochondrial mtDNA and mRNA | [157] | |
Fibrates | Activates AMPK and PGC-1α | [158] | |
Recombinant TFAM | Increases respiration and mitochondrial biogenesis | ||
Autophagy/ Mitophagy | Melatonin | Counteracts oxidative stress, and prevents collapse of mitochondrial membrane potential; accumulates within mitochondria to prevent cardiolipin peroxidation in order to maintain cardiolipin interaction with autophagosomes via LC3II | |
Urolithin A | Induces expression of mitophagy proteins, including full-length PINK1, Parkin, OPTN; p-ULK1, LC3B-II, Beclin1, Bcl2L13, AMBRA1, and FUNDC1 in SH-SY5Y cells; induces expression of full-length PINK1 in brain tissues of mice | ||
Actinonin | Induces expression of mitophagy proteins, including full-length PINK1, Parkin, OPTN; p-ULK1, LC3B-II, Beclin1, Bcl2L13, AMBRA1, and FUNDC1 in SH-SY5Y cells; induces expression of full-length PINK1 in brain tissues of mice | ||
Rapamycin | Induces macro-autophagy by direct binding and inhibition of mTOR; stimulates AMPK; extends lifespan in mice in an ULK1-dependent manner | ||
Metformin | Induces autophagy/mitophagy via SIRT1, IGF-1, and mTORC1, or via Parkin-mediated mitophagy | ||
Spermidine | Induces mitophagy through multiple pathways, involving the ATM-PINK1-Parkin pathway, the Nrf2-SKN-1 pathway, and through activation of AMPK and inhibition of mTOR; inhibits EP300; induces BNIP3, CTSL, and ATGs | ||
Torin1 | Induces autophagy by inhibiting the kinase domains of two TORC complexes | ||
Lithium | Removes altered mitochondria and protein aggregates | [178] |