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

Author

Listed:
  • 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
    Institute of Biophysics (IBF), CNR)

  • 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)

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.

Suggested Citation

  • Luca Muzio & Riccardo Sirtori & Davide Gornati & Simona Eleuteri & Andrea Fossaghi & Diego Brancaccio & Leonardo Manzoni & Linda Ottoboni & Luca De Feo & Angelo Quattrini & Eloise Mastrangelo & Luca S, 2020. "Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17524-7
    DOI: 10.1038/s41467-020-17524-7
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    Cited by:

    1. James L. Daly & Chris M. Danson & Philip A. Lewis & Lu Zhao & Sara Riccardo & Lucio Filippo & Davide Cacchiarelli & Daehoon Lee & Stephen J. Cross & Kate J. Heesom & Wen-Cheng Xiong & Andrea Ballabio , 2023. "Multi-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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