Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.
Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis / Muzio, L.; Sirtori, R.; Gornati, D.; Eleuteri, S.; Fossaghi, A.; Brancaccio, D.; Manzoni, L.; Ottoboni, L.; Feo, L. D.; Quattrini, A.; Mastrangelo, E.; Sorrentino, L.; Scalone, E.; Comi, G.; Marinelli, L.; Riva, N.; Milani, M.; Seneci, P.; Martino, G.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 11:1(2020), p. 3848. [10.1038/s41467-020-17524-7]
Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis
Sirtori R.;Comi G.;Martino G.
2020-01-01
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a fatal disease characterized by the degeneration of upper and lower motor neurons (MNs). We find a significant reduction of the retromer complex subunit VPS35 in iPSCs-derived MNs from ALS patients, in MNs from ALS post mortem explants and in MNs from SOD1G93A mice. Being the retromer involved in trafficking of hydrolases, a pathological hallmark in ALS, we design, synthesize and characterize an array of retromer stabilizers based on bis-guanylhydrazones connected by a 1,3-phenyl ring linker. We select compound 2a as a potent and bioavailable interactor of VPS35-VPS29. Indeed, while increasing retromer stability in ALS mice, compound 2a attenuates locomotion impairment and increases MNs survival. Moreover, compound 2a increases VPS35 in iPSCs-derived MNs and shows brain bioavailability. Our results clearly suggest the retromer as a valuable druggable target in ALS.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
