Neuronal polyunsaturated fatty acids are protective in ALS/FTD.

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• C9orf72 repeat expansion is the leading genetic cause of ALS/FTD.
• Altered lipid metabolism is implicated in neurodegenerative diseases.
• Understanding molecular pathways in ALS/FTD is crucial for developing treatments.

Purpose of the Study:

• To investigate the role of fatty acid and lipid metabolism in C9orf72-linked ALS/FTD.
• To identify specific lipid alterations in ALS/FTD models and patient tissues.
• To explore the therapeutic potential of polyunsaturated fatty acids (PUFAs) in ALS/FTD.

Main Methods:

• Transcriptomic analysis in Drosophila models of C9orf72 repeat expansion.
• Lipidomic profiling of Drosophila, iPS cell neurons, and postmortem brain tissue.
• Genetic manipulation (overexpression of fatty acid desaturases) in Drosophila and iPS cells.
• Assessment of survival and neuronal death in response to PUFA supplementation and genetic interventions.

Main Results:

• A conserved transcriptomic signature of reduced fatty acid and lipid metabolism was observed in C9orf72 ALS/FTD models and human tissues.
• A specific reduction in phospholipids containing polyunsaturated fatty acids (PUFAs) was identified.
• Feeding PUFAs to flies provided a modest survival benefit.
• Neuronal overexpression of fatty acid desaturases significantly extended lifespan in flies and protected iPS cell neurons from death.

Conclusions:

• Neuronal fatty acid saturation is implicated in the pathogenesis of ALS/FTD.
• Increasing neuronal PUFA levels represents a promising therapeutic strategy for ALS/FTD.
• Targeting lipid metabolism pathways may offer novel treatment avenues for neurodegenerative diseases.