Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives

Abstract

Chaperone-mediated autophagy (CMA) contributes to cellular quality control and the cellular response to stress through the selective degradation of cytosolic proteins in lysosomes. Decrease in CMA activity occurs in aging and in age-related disorders (for example, neurodegenerative diseases and diabetes). Although prevention of this age-dependent decline through genetic manipulation in mouse has proven beneficial, chemical modulation of CMA is not currently possible, due in part to the lack of information on the signaling mechanisms that modulate this pathway. In this work, we report that signaling through the retinoic acid receptor alpha (RARα) inhibits CMA and apply structure-based chemical design to develop synthetic derivatives of all-trans-retinoic acid (ATRA) to specifically neutralize this inhibitory effect. We demonstrate that chemical enhancement of CMA protects cells from oxidative stress and from proteotoxicity, supporting a potential therapeutic opportunity when reduced CMA contributes to cellular dysfunction and disease.

Chaperone-mediated autophagy: roles in disease and aging

“…In addition, a sequence variation in the promoter region of LAMP-2 identified recently in a PD patient [61], opens up the possibility that alterations in CMA components may be behind some forms of PD. The fact that both chemical [31] and genetic [62] upregulation of CMA have been shown to be capable of alleviating cellular toxicity associated with pathogenic forms of α-synuclein supports that the changes in CMA observed in PD are not a mere consequence of the disease, but that rather they contribute to pathogenesis.…”

“…While genetic interventions may be unfeasible or highly challenging in the elderly, recent studies have provided more amenable options through the modulation of dietary lipid intake and the development of retinoic acid derivatives that specifically regulate CMA without affecting other autophagic pathways [31,68]. Inverse interventions may be considered under those instances such as cancer in which blockage of CMA may be useful.…”

“…To date, the best way to block this autophagic pathway is through knock-down or knock-out of LAMP-2A, because manipulation of any of the other CMA components (hsc70, hsp90, GFAP or EF1α), is usually more difficult to interpret due to the additional cellular functions of these proteins. Although chemical activators of CMA are now available [31], considerably less progress has been made in the identification of specific inhibitors of this pathway. Unfortunately, some of the small molecules initially described to modulate CMA [44] have proven to be rather non-specific and to affect the activity of other cellular quality-control mechanisms, again making interpretation of results obtained with these drugs difficult.…”

“…Levels of LAMP-2A can be regulated through transcriptional upregulation, as in the case of oxidative stress [28], or through changes in the degradation rate of LAMP-2A at the lysosomal membrane, as occurs when CMA is upregulated during prolonged starvation [29,30]. Although there is still relatively limited information about the signaling pathways that contribute to modulating CMA activity, a negative regulatory effect of the nuclear receptor, retinoic acid receptor α, on CMA has been recently described [31]. Signaling through this receptor inhibits, among others, LAMP-2A transcription and this blockage is released when CMA upregulation is required.…”

Chaperone-mediated autophagy: roles in neuroprotection

“…Consistent with the involvement of CMA in HD, the activity of this pathway appears to increase in mouse models of HD. oxidative stress and proteotoxicity [67] . …”