AR7は非典型的なレチノイン酸受容体α (RARα)拮抗剤である[1]。AR7はRARαに拮抗し、CMAに対する拮抗を解除し、よってLAMP2AとCMAの活性を著しく増強し、誤って折り畳まれたタンパク質や凝集したタンパク質の選択的分解を促進する[2-3]。AR7はよくパーキンソン病の治療に使われる[4]。
初代皮質ニューロンで、AR7 (0-20μM；21日間)は、皮質ニューロンの長期培養物で、細胞内と細胞外SNCAオリゴマーの進行性蓄積を軽減する[5]。SN4741細胞で、AR7 (20μM；24時間)は、シャペロン媒介のオートファジー（CMA）を活性化し、脂質生物合成酵素Fasnの分解を促進することで、Wdr45欠乏モデルで、脂質滴の蓄積を減らす[6]。
C57BL/6マウスで、AR7 (10mg/kg；腹腔内注射；6時間)は、ジクロフェナク誘発性脂肪肝を軽減する[7]。ヘテロ接合性の子孫マウスで、AR7 (10mg/kg；腹腔内注射；6週間)の投与は、肝臓SERPINA1E342K/ATZの排泄を促進し、肝臓SERPINA1E342K/ATZ凝集病理を軽減する[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.