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Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-17524-7

2041-1723

Luca Muzio, Riccardo Sirtori, Davide Gornati, Simona Eleuteri, Andrea Fossaghi, Diego Brancaccio, Leonardo Manzoni, Linda Ottoboni, Luca De Feo, Angelo Quattrini, Eloise Mastrangelo, Luca Sorrentino, Emanuele Scalone, Giacomo P. Comi, Luciana Marinelli, Nilo Riva, Mario Milani, Pierfausto Seneci, Gianvito Martino,

Biochemical Acid Research Studies

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.