AR7 is an atypical retinoic acid receptor α (RARα) antagonist [1]. AR7 antagonizes RARα to relieve its inhibition of CMA, thereby significantly enhancing LAMP2A and CMA activity and promoting the selective degradation of misfolded or aggregated proteins [2-3]. AR7 is commonly used to treat Parkinson's disease [4].
In primary cortical neurons, AR7 (0-20μM; 21d) attenuates the progressive accumulation of intracellular and extracellular SNCA oligomers in long-term cultures of cortical neurons [5]. In SN4741 cells, AR7 (20μM; 24h) reduces lipid droplet accumulation in the Wdr45-deficient model by activating chaperone-mediated autophagy (CMA) and promoting the degradation of the lipid biosynthesis enzyme Fasn [6].
In C57BL/6 mice, AR7 (10mg/kg; ip; 6h) alleviates diclofenac-induced hepatic steatosis [7]. In heterozygous offspring mice, administration of AR7 (10mg/kg; ip; 6 weeks) promotes hepatic SERPINA1E342K/ATZ elimination and mitigates hepatic SERPINA1E342K/ATZ aggregation pathology [8].
References:
[1]. Anguiano J, Garner T P, Mahalingam M, et al. Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives[J]. Nature chemical biology, 2013, 9(6): 374-382.
[2]. Bourdenx M, Martín-Segura A, Scrivo A, et al. Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome[J]. Cell, 2021, 184(10): 2696-2714. e25.
[3]. Wang Y T, Lu J H. Chaperone-mediated autophagy in neurodegenerative diseases: molecular mechanisms and pharmacological opportunities[J]. Cells, 2022, 11(14): 2250.
[4]. Chen J, Mao K, Yu H, et al. p38-TFEB pathways promote microglia activation through inhibiting CMA-mediated NLRP3 degradation in Parkinson's disease[J]. Journal of neuroinflammation, 2021, 18(1): 295.
[5]. Ho P W L, Leung C T, Liu H, et al. Age-dependent accumulation of oligomeric SNCA/α-synuclein from impaired degradation in mutant LRRK2 knockin mouse model of Parkinson disease: role for therapeutic activation of chaperone-mediated autophagy (CMA)[J]. Autophagy, 2020, 16(2): 347-370.
[6]. Xiong Q, Sun H, Wang Y, et al. Lipid droplet accumulation in Wdr45-deficient cells caused by impairment of chaperone-mediated autophagic degradation of Fasn[J]. Lipids in Health and Disease, 2024, 23(1): 91.
[7]. Lee W, Kim H Y, Choi Y J, et al. SNX10-mediated degradation of LAMP2A by NSAIDs inhibits chaperone-mediated autophagy and induces hepatic lipid accumulation[J]. Theranostics, 2022, 12(5): 2351.
[8]. Lin J, Wei X, Dai Y, et al. Chaperone-mediated autophagy degrades SERPINA1E342K/α1-antitrypsin Z variant and alleviates cell stress[J]. Autophagy, 2025: 1-18.