Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson's disease

Abstract

Parkinson's disease (PD), known as one of the most universal neurodegenerative diseases, is a serious threat to the health of the elderly. The current treatment has been demonstrated to relieve symptoms, and the discovery of new small-molecule compounds has been regarded as a promising strategy. Of note, the homeostasis of the autolysosome pathway (ALP) is closely associated with PD, and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD. Thus, pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far. In this review, we focus on summarizing several autophagy-associated targets, such as AMPK, mTORC1, ULK1, IMPase, LRRK2, beclin-1, TFEB, GCase, ERRα, C-Abelson, and as well as their relevant small-molecule compounds in PD models, which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future.

Keywords: 3-MA, 3-methyladenine; 5-HT2A, Serotonin 2A; 5-HT2C, serotonin 2C; A2A, adenosine 2A; AADC, aromatic amino acid decarboxylase; ALP, autophagy-lysosomal pathway; AMPK, 5ʹAMP-activated protein kinase; ATG, autophagy related protein; ATP13A2, ATPase cation transporting 13A2; ATTEC, autophagosome-tethering compound; AUC, the area under the curve; AUTAC, autophagy targeting chimera; Autophagy; BAF, bafilomycinA1; BBB, blood−brain barrier; CL, clearance rate; CMA, chaperone-mediated autophagy; CNS, central nervous system; COMT, catechol-O-methyltransferase; DA, dopamine; DAT, dopamine transporter; DJ-1, Parkinson protein 7; DR, dopamine receptor; ER, endoplasmic reticulum; ERRα, estrogen-related receptor alpha; F, oral bioavailability; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GBA, glucocerebrosidase β acid; GWAS, genome-wide association study; HDAC6, histone deacetylase 6; HSC70, heat shock cognate 71 kDa protein; HSPA8, heat shock 70 kDa protein 8; IMPase, inositol monophosphatase; IPPase, inositol polyphosphate 1-phosphatase; KI, knockin; LAMP2A, lysosome-associated membrane protein 2 A; LC3, light chain 3; LIMP-2, lysosomal integrated membrane protein-2; LRRK2, leucine-rich repeat sequence kinase 2; LRS, leucyl-tRNA synthetase; LUHMES, lund human mesencephalic; Lamp2a, type 2A lysosomal-associated membrane protein; MAO-B, monoamine oxidase B; MPP+, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine; MYCBP2, MYC-binding protein 2; NMDA, N-methyl-d-aspartic acid; ONRs, orphan nuclear receptors; PD therapy; PD, Parkinson's disease; PDE4, phosphodiesterase 4; PI3K, phosphatidylinositol 3-kinase; PI3P, phosphatidylinositol 3-phosphate; PINK1, PTEN-induced kinase 1; PLC, phospholipase C; PREP, prolyl oligopeptidase; Parkin, parkin RBR E3 ubiquitin−protein ligase; Parkinson's disease (PD); ROS, reactive oxygen species; SAR, structure–activity relationship; SAS, solvent accessible surface; SN, substantia nigra; SNCA, α-synuclein gene; SYT11, synaptotagmin 11; Small-molecule compound; TFEB, transcription factor EB; TSC2, tuberous sclerosis complex 2; Target; ULK1, UNC-51-like kinase 1; UPS, ubiquitin−proteasome system; mAChR, muscarinic acetylcholine receptor; mTOR, the mammalian target of rapamycin; α-syn, α-synuclein.