1. Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis.
- Author
-
Muzio L, Sirtori R, Gornati D, Eleuteri S, Fossaghi A, Brancaccio D, Manzoni L, Ottoboni L, Feo L, Quattrini A, Mastrangelo E, Sorrentino L, Scalone E, Comi G, Marinelli L, Riva N, Milani M, Seneci P, and Martino G
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis pathology, Animals, Brain drug effects, Brain metabolism, Brain pathology, Cell Differentiation, Cell Survival drug effects, Disease Models, Animal, Humans, Hydrazones chemical synthesis, Induced Pluripotent Stem Cells cytology, Induced Pluripotent Stem Cells drug effects, Induced Pluripotent Stem Cells metabolism, Locomotion drug effects, Locomotion physiology, Male, Mice, Mice, Transgenic, Motor Neurons metabolism, Motor Neurons pathology, Neuroprotection drug effects, Neuroprotective Agents chemical synthesis, Protein Binding drug effects, Protein Multimerization, Structure-Activity Relationship, Superoxide Dismutase-1 genetics, Superoxide Dismutase-1 metabolism, Vesicular Transport Proteins metabolism, Amyotrophic Lateral Sclerosis drug therapy, Hydrazones pharmacology, Motor Neurons drug effects, Neuroprotective Agents pharmacology, Vesicular Transport Proteins genetics
- 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.
- Published
- 2020
- Full Text
- View/download PDF