Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis
Luca Muzio1, Riccardo Sirtori2, Davide Gornati3
1INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milano, Italy. luca.muzio@hsr.it.
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.
Insights
Researchers identified reduced VPS35 in Amyotrophic Lateral Sclerosis (ALS). They developed a compound, 2a, that stabilizes the retromer complex, improving motor neuron survival and function in ALS models.
Area of Science:
- Neuroscience
- Molecular Biology
- Drug Discovery
Background:
- Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease marked by motor neuron loss.
- Reduced levels of the retromer complex subunit VPS35 are observed in ALS patients and models.
- The retromer complex is crucial for cellular trafficking, and its dysfunction is implicated in ALS pathology.
Purpose of the Study:
- To investigate the role of the retromer complex in Amyotrophic Lateral Sclerosis (ALS).
- To design and synthesize novel retromer stabilizers as potential therapeutic agents for ALS.
- To evaluate the efficacy of a lead compound (2a) in preclinical ALS models.
Main Methods:
- Analysis of VPS35 levels in induced pluripotent stem cell (iPSC)-derived motor neurons (MNs) from ALS patients and post-mortem tissues.
- Synthesis and characterization of bis-guanylhydrazone compounds as retromer stabilizers.
- Assessment of compound 2a's effects on retromer stability, MN survival, and motor function in SOD1G93A ALS mice.
- Evaluation of compound 2a's bioavailability in the brain.
Main Results:
- A significant reduction in VPS35 was confirmed in ALS patient-derived MNs and ALS mouse models.
- Compound 2a effectively stabilized the retromer complex and interacted with VPS35-VPS29.
- Treatment with compound 2a improved motor function and increased MN survival in ALS mice.
- Compound 2a demonstrated brain bioavailability and increased VPS35 levels in iPSC-derived MNs.
Conclusions:
- The retromer complex, particularly VPS35, is a critical factor in Amyotrophic Lateral Sclerosis (ALS) pathogenesis.
- Compound 2a represents a promising therapeutic candidate for ALS by stabilizing the retromer complex.
- Targeting the retromer offers a viable druggable strategy for treating ALS.
