Table 1.

Small-molecule compounds enhance TFEB activity and lysosome biogenesis

Compounds	Structure	Mechanisms	Animal models of neurodegenerative diseases	Effects on neurodegenerative diseases	References
Catalpol		Activates AMPK and inhibits mTOR	APP/PS1-AD mice	Reduces Aβ load; alleviates cognitive impairments	Ren et al., 2019; Du et al., 2022
Curcumin		Inhibits mTORC1	5xFAD-AD mice; 3xTg-AD mice	Attenuates both APP and Tau pathology; improves cognitive deficits	Song et al., 2020
Compound E4		Inhibits the Akt-mTORC1 pathway	N.A.	N.A.	Wang et al., 2020c
HEP14		Directly binds to PKCα and PKCδ, thus activating PKCα and PKCδ	APP/PS1-AD mice	Reduces Aβ plaques; decreases Aβ40 and Aβ42	Li et al., 2016
Itaconate		Enhances the alkylation of TFEB at site C212	N.A.	N.A.	Zhang et al., 2022b
LH2-051		Directly binds to dopamine transporter (DAT) and inhibits DAT function	APP/PS1-AD mice	Reduces Aβ plaques; decreases Aβ40 and Aβ42; alleviates cognitive impairments	Yin et al., 2022
MSL		Directly binds to and stabilizes calcineurin A	N.A.	N.A.	Lim et al., 2018
Oblongifolin C		Inhibits mTORC1	N.A.	N.A.	Wu et al., 2019
Procyanidin B2		Potentially binds to TFEB	N.A.	N.A.	Su et al., 2018
Quercetin		Directly inhibits mTORC1	3xTg-AD mice; PD rats (rats were injected with 6-OHDA in striatum); HD rats (rats were injected with 3-NP)	Decreases Aβ and protects cognitive function; increases BDNF level and enhances cognitive effects; corrects movement disturbances and anxiety	Chakraborty et al., 2014; Huang et al., 2018; Paula et al., 2019; Naghizadeh et al., 2021
Rapamycin		Directly binds to mTOR and inhibits mTORC1	3xTg-AD mice; PD mice (C57BL/6 mice were intraperitoneally injected with MPTP)	Reduces Aβ plaques and Tau pathology; protects substantia nigral neurons	Malagelada et al., 2010; Majumder et al., 2011; Battaglioni et al., 2022
SAHA		Enhances the acetylation of TFEB at sites K91, K103, K116, and K430	Mice with insulin resistance-induced cognitive deficit; R6/2-HD mice	Improves cognitive functions; reduces SDS-insoluble aggregate load	Mielcarek et al., 2011; Sharma and Taliyan, 2016; Zhang et al., 2018
Siramesine		Inhibits mTORC1	N.A.	N.A.	Zhitomirsky et al., 2018
Sulforaphane		Increases intracellular ROS, then stimulates Ca2+ release	PS1V97L-AD mice	Inhibits the generation of Aβ; alleviates the cognitive deficits	Hou et al., 2018; Li et al., 2021
Sunitinib		Inhibits mTORC1	AD2576APPSwe-AD mice; 3xTg-AD mice	Reduces Aβ; improves cognitive function	Grammas et al., 2014; Zhitomirsky et al., 2018
Torin-1		Effectively blocks phosphorylation of mTOR (both mTORC1 and mTORC2)	PD mice (C57BL/6J female mice were injected with 6-OHDA in striatum)	Alleviates loss of dopaminergic neurons	Thoreen et al., 2009; Zhuang et al., 2020
Trehalose		Increases transient lysosomal membrane permeability, and releases Ca2+ from the lysosomes to activate the phosphatase PPP3/calcineurin	APP23-AD mice; R6/2-HD mice	Reduces Aβ generation and plaque formation; decreases polyglutamine aggregates improves motor function	Tanaka et al., 2004; Rusmini et al., 2019; Liu et al., 2020
Trichostatin A (TSA)		Enhances the acetylation of TFEB at sites K116, K236, K237, and K431, and decreases TFEB ubiquitination at site K347	APP/PS1-AD mice	Reduces Aβ plaques; decreases Aβ40 and Aβ42; improves learning, memory, and cognitive functions	Li et al., 2022
Tripterine		Inhibits mTORC1, thus inducing TFEB dephosphorylation at sites S142 and S211	P301S Tau-AD mice; 3xTg-AD mice	Attenuates Tau pathology and cognitive deficits	Yang et al., 2022

6-OHDA: 6-Hydroxydopamine; AD: Alzheimer’s disease; AMPK: AMP-activated protein kinase; APP: amyloid precursor protein; Aβ: amyloid beta; BDNF: brain-derived neurotrophic factor; HD: Huntington’s disease; MPTP: 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine; mTOR: mammalian target of rapamycin; N.A.: not available; PD: Parkinson’s disease; PKC: protein kinase C; ROS: reactive oxygen species; SDS: sodium dodecyl sulfate; TFEB: transcription factor EB.