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

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, Giancarlo Comi, Luciana Marinelli, Nilo Riva, Mario Milani, Pierfausto Seneci and Gianvito Martino
Additional contact information
Luca Muzio: INSPE—Institute of Experimental Neurology, San Raffaele Scientific Institute
Riccardo Sirtori: INSPE—Institute of Experimental Neurology, San Raffaele Scientific Institute
Davide Gornati: University of Milan
Simona Eleuteri: INSPE—Institute of Experimental Neurology, San Raffaele Scientific Institute
Andrea Fossaghi: INSPE—Institute of Experimental Neurology, San Raffaele Scientific Institute
Diego Brancaccio: University of Naples “Federico II”
Leonardo Manzoni: Institute of Molecular Science and Technology (ISTM), CNR
Linda Ottoboni: INSPE—Institute of Experimental Neurology, San Raffaele Scientific Institute
Luca De Feo: INSPE—Institute of Experimental Neurology, San Raffaele Scientific Institute
Angelo Quattrini: INSPE—Institute of Experimental Neurology, San Raffaele Scientific Institute
Eloise Mastrangelo: Institute of Biophysics (IBF), CNR
Luca Sorrentino: Institute of Biophysics (IBF), CNR
Emanuele Scalone: University of Milan
Giancarlo Comi: INSPE—Institute of Experimental Neurology, San Raffaele Scientific Institute
Luciana Marinelli: University of Naples “Federico II”
Nilo Riva: INSPE—Institute of Experimental Neurology, San Raffaele Scientific Institute
Mario Milani: Institute of Biophysics (IBF), CNR
Pierfausto Seneci: University of Milan
Gianvito Martino: INSPE—Institute of Experimental Neurology, San Raffaele Scientific Institute

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17524-7

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