Metabolic Reprogramming in Amyotrophic Lateral Sclerosis.

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Metabolic Research

Background:

• Mitochondrial dysfunction is a key feature of amyotrophic lateral sclerosis (ALS).
• Early-stage neurometabolic alterations in ALS remain poorly understood.
• Investigating bioenergetic and proteomic changes is crucial for understanding disease progression.

Purpose of the Study:

• To investigate early-stage bioenergetic and proteomic alterations in ALS motor neurons and patient fibroblasts.
• To identify novel metabolic pathways and potential therapeutic targets in ALS.
• To compare molecular changes between ALS mouse models and human patients.

Main Methods:

• Proteomic analysis of presymptomatic SODG93A mouse motor neurons.
• Assessment of oxidative phosphorylation coupling efficiency and mitochondrial network morphology.
• Functional studies involving fatty acid oxidation (FAO) and uncoupling protein 2 (UCP2) inhibition.
• Comparative molecular analysis of mouse motor neurons and human ALS skin fibroblasts.

Main Results:

• Presymptomatic ALS motor neurons exhibit altered oxidative phosphorylation and fragmented mitochondrial networks.
• A distinct metabolic signature in ALS motor neurons shows upregulation of energy-transducing enzymes, including FAO and ketogenic components.
• FAO inhibition selectively impaired ALS motor neuron viability, while UCP2 inhibition restored ATP levels and mitochondrial morphology.
• Conserved molecular changes were identified in human ALS fibroblasts and mouse motor neurons, particularly in protein translation, folding, and cell adhesion.

Conclusions:

• Early-stage ALS involves significant bioenergetic alterations in motor neurons, linked to fatty acid oxidation and uncoupling protein 2.
• Targeting FAO or UCP2 may offer novel therapeutic strategies for ALS.
• Comparative analysis reveals conserved molecular pathways affected in ALS across species, providing insights into disease mechanisms.