Neuroprotective Effects of RNS60 in TDP-43 Pathology-Associated Amyotrophic Lateral Sclerosis.

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Neurodegenerative Diseases

Background:

• TDP-43 protein aggregates are a hallmark of amyotrophic lateral sclerosis (ALS) pathology in the brain.
• RNS60, an experimental therapy, has previously shown benefits in mitochondrial function in preclinical models.
• Investigating RNS60's effects on mitochondrial stability and upper motor neuron (UMN) health in a TDP-43 ALS mouse model is crucial.

Purpose of the Study:

• To determine if RNS60 treatment can improve mitochondrial stability and UMN health in a TDP-43 mouse model of ALS.
• To assess RNS60's impact on mitochondrial structure, function, and neuromuscular junction (NMJ) integrity.
• To evaluate RNS60's effects on neuroinflammation, specifically astrogliosis and microgliosis.

Main Methods:

• prpTDP-43A315T-UeGFP and WT-UeGFP mice were treated with RNS60 or placebo from postnatal day 30 to 90.
• Immunocytochemistry was used to quantify astrogliosis and microgliosis in the brain and spinal cord.
• Mitochondrial ultrastructure, function (membrane polarization), and NMJ integrity were assessed using electron microscopy and flow cytometry.

Main Results:

• RNS60 significantly reduced defective mitochondria in both UMNs and spinal motor neurons.
• The treatment increased mitochondrial membrane polarization and preserved NMJ integrity in leg and diaphragm muscles.
• RNS60 also reduced astrogliosis and microgliosis in the motor cortex and spinal cord, protecting UMNs.

Conclusions:

• RNS60 treatment demonstrates neuroprotective effects in a TDP-43 mouse model of ALS.
• The findings suggest RNS60 promotes motor neuron health by enhancing mitochondrial function and integrity.
• RNS60's ability to reduce gliosis and preserve NMJ function indicates its therapeutic potential for ALS.