1. Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis
- Author
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Muzio, Luca, Sirtori, Riccardo, Gornati, Davide, Eleuteri, Simona, Fossaghi, Andrea, Brancaccio, Diego, Manzoni, Leonardo, Ottoboni, Linda, De Feo, Quattrini, Angelo, Mastrangelo, Eloise, Sorrentino, Scalone, Emanuele, Comi, Giancarlo, Marinelli, Luciana, Riva, Nilo, Milani, Mario, Seneci, Pierfausto, Martino, Gianvito, 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., Muzio, Luca, Sirtori, Riccardo, Gornati, Davide, Eleuteri, Simona, Fossaghi, Andrea, Brancaccio, Diego, Manzoni, Leonardo, Ottoboni, Linda, Feo, Luca De, Quattrini, Angelo, Mastrangelo, Eloise, Sorrentino, Luca, Scalone, Emanuele, Comi, Giancarlo, Marinelli, Luciana, Riva, Nilo, Milani, Mario, Seneci, Pierfausto, and Martino, Gianvito
- Subjects
Male ,0301 basic medicine ,Motor neuron ,ALPHA-SYNUCLEIN ,Retromer ,Cellular differentiation ,Vesicular Transport Proteins ,General Physics and Astronomy ,Induced Pluripotent Stem Cell ,Mice ,VPS35 ,Superoxide Dismutase-1 ,0302 clinical medicine ,GOLGI-APPARATUS ,Amyotrophic lateral sclerosis ,lcsh:Science ,TRANSGENIC MICE ,Motor Neurons ,Multidisciplinary ,Chemistry ,Brain ,Cell Differentiation ,MOUSE MODEL ,Hydrazone ,Neuroprotection ,Cell biology ,Neuroprotective Agents ,ZN SUPEROXIDE-DISMUTASE ,Protein aggregation ,CU ,Locomotion ,Human ,Protein Binding ,Cell Survival ,Science ,Transgene ,Protein subunit ,Neuroprotective Agent ,Induced Pluripotent Stem Cells ,Mice, Transgenic ,Article ,General Biochemistry, Genetics and Molecular Biology ,Structure-Activity Relationship ,03 medical and health sciences ,medicine ,Animals ,Humans ,Organelles ,COMPLEX ,ENDOSOME ,Animal ,Amyotrophic Lateral Sclerosis ,Hydrazones ,MAMMALIAN RETROMER ,General Chemistry ,medicine.disease ,Retromer complex ,Disease Models, Animal ,030104 developmental biology ,MOTOR-NEURON DEGENERATION ,lcsh:Q ,Protein Multimerization ,030217 neurology & neurosurgery ,Amyotrophic Lateral Sclerosi - 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., ALS is a neurodegenerative disease characterized by loss of motor neurons. Here, the authors showed that reduced levels of the VSP35 subunit in the retromer complex is a conserved ALS feature and identified a new lead compound increasing retromer stability ameliorating the disease phenotype.
- Published
- 2020