3-iodothyronamine (T1AM) and the recently developed analog SG-2 are rapidly emerging as promising multi-target neuroprotective ligands able to reprogram lipid metabolism and to produce memory enhancement in mice. To elucidate the molecular mechanisms underlying the multi-target effects of these novel drug candidates, here we investigated whether the modulation of SIRT6, known to play a key role in reprogramming energy metabolism, might also drive the activation of clearing pathways, such as autophagy and ubiquitine-proteasome (UP), as further mechanisms against neurodegeneration. We show that both T1AM and SG-2 increase autophagy in U87MG cells by inducing the expression of SIRT6, which suppresses Akt activity thus leading to mTOR inhibition. This effect was concomitant with down-regulation of autophagy-related genes, including Hif1α, p53 and mTOR. Remarkably, when mTOR was inhibited a concomitant activation of autophagy and UP took place in U87MG cells. Since both compounds activate autophagy, which is known to sustain long term potentiation (LTP) in the entorhinal cortex (EC) and counteracting AD pathology, further electrophysiological studies were carried out in a transgenic mouse model of AD. We found that SG-2 was able to rescue LTP with an efficacy comparable to T1AM, further underlying its potential as a novel pleiotropic agent for neurodegenerative disorders treatment.

Endogenous 3-iodothyronamine (T1Am) and synthetic thyronamine-like analog SG-2 act as novel pleiotropic neuroprotective agents through the modulation of SIRT6 / Bellusci, L.; Runfola, M.; Carnicelli, V.; Sestito, S.; Fulceri, F.; Santucci, F.; Lenzi, P.; Fornai, F.; Rapposelli, S.; Origlia, N.; Zucchi, R.; Chiellini, G.. - In: MOLECULES. - ISSN 1420-3049. - 25:5(2020), p. 1054. [10.3390/molecules25051054]

Endogenous 3-iodothyronamine (T1Am) and synthetic thyronamine-like analog SG-2 act as novel pleiotropic neuroprotective agents through the modulation of SIRT6

Sestito S.;
2020-01-01

Abstract

3-iodothyronamine (T1AM) and the recently developed analog SG-2 are rapidly emerging as promising multi-target neuroprotective ligands able to reprogram lipid metabolism and to produce memory enhancement in mice. To elucidate the molecular mechanisms underlying the multi-target effects of these novel drug candidates, here we investigated whether the modulation of SIRT6, known to play a key role in reprogramming energy metabolism, might also drive the activation of clearing pathways, such as autophagy and ubiquitine-proteasome (UP), as further mechanisms against neurodegeneration. We show that both T1AM and SG-2 increase autophagy in U87MG cells by inducing the expression of SIRT6, which suppresses Akt activity thus leading to mTOR inhibition. This effect was concomitant with down-regulation of autophagy-related genes, including Hif1α, p53 and mTOR. Remarkably, when mTOR was inhibited a concomitant activation of autophagy and UP took place in U87MG cells. Since both compounds activate autophagy, which is known to sustain long term potentiation (LTP) in the entorhinal cortex (EC) and counteracting AD pathology, further electrophysiological studies were carried out in a transgenic mouse model of AD. We found that SG-2 was able to rescue LTP with an efficacy comparable to T1AM, further underlying its potential as a novel pleiotropic agent for neurodegenerative disorders treatment.
2020
Endogenous 3-iodothyronamine (T1Am) and synthetic thyronamine-like analog SG-2 act as novel pleiotropic neuroprotective agents through the modulation of SIRT6 / Bellusci, L.; Runfola, M.; Carnicelli, V.; Sestito, S.; Fulceri, F.; Santucci, F.; Lenzi, P.; Fornai, F.; Rapposelli, S.; Origlia, N.; Zucchi, R.; Chiellini, G.. - In: MOLECULES. - ISSN 1420-3049. - 25:5(2020), p. 1054. [10.3390/molecules25051054]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11388/236197
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 16
  • ???jsp.display-item.citation.isi??? 14
social impact