In:
Nature Communications, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2020-07-31)
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.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-020-17524-7
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2020
detail.hit.zdb_id:
2553671-0
Permalink