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 / L. Muzio, R. Sirtori, D. Gornati, S. Eleuteri, A. Fossaghi, D. Brancaccio, L. Manzoni, L. Ottoboni, L.D. Feo, A. Quattrini, E. Mastrangelo, L. Sorrentino, E. Scalone, G. Comi, L. Marinelli, N. Riva, M. Milani, P. Seneci, G. Martino. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 11:1(2020 Jul 31), pp. 3848.1-3848.17.

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

D. Gornati;D. Brancaccio;L. Manzoni;L. Ottoboni;E. Mastrangelo;L. Sorrentino;E. Scalone;G. Comi;P. Seneci;
2020

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.
Settore MED/26 - Neurologia
Settore BIO/10 - Biochimica
Settore CHIM/06 - Chimica Organica
31-lug-2020
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/756726
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