Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6
Lorenza Bellusci,
Massimiliano Runfola,
Vittoria Carnicelli,
Simona Sestito,
Federica Fulceri,
Filippo Santucci,
Paola Lenzi,
Francesco Fornai,
Simona Rapposelli,
Nicola Origlia,
Riccardo Zucchi,
Grazia Chiellini
Affiliations
Lorenza Bellusci
Laboratory of Biochemistry, Department of Pathology, University of Pisa, 56100 Pisa, Italy
Massimiliano Runfola
Laboratory of Medicinal Chemistry, Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Vittoria Carnicelli
Laboratory of Biochemistry, Department of Pathology, University of Pisa, 56100 Pisa, Italy
Simona Sestito
Laboratory of Biochemistry, Department of Pathology, University of Pisa, 56100 Pisa, Italy
Federica Fulceri
Department of Clinical and Experimental Medicine, University of Pisa, 56100 Pisa, Italy
Filippo Santucci
Sant’Anna School of Advanced Studies, 56127 Pisa, Italy
Paola Lenzi
Unit of Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
Francesco Fornai
Unit of Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
Simona Rapposelli
Laboratory of Medicinal Chemistry, Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Nicola Origlia
National Research Council (CNR), Institute of Neuroscience, 56124 Pisa, Italy
Riccardo Zucchi
Laboratory of Biochemistry, Department of Pathology, University of Pisa, 56100 Pisa, Italy
Grazia Chiellini
Laboratory of Biochemistry, Department of Pathology, University of Pisa, 56100 Pisa, Italy
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.
