Effects of Fatty Acid Desaturases on Neurodegeneration in a Mouse Model of C9orf72-Associated Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Abstract

Amyotrophic lateral sclerosis and frontotemporal dementia share overlapping clinical, pathological, and genetic features, most prominently the C9orf72 G₄C₂ hexanucleotide repeat expansion. Dysregulated lipid metabolism has emerged as a contributing factor, with evidence suggesting that polyunsaturated fatty acids influence neuronal survival and inflammatory responses. Despite preclinical data supporting neuroprotective roles of endogenous PUFA synthesis, it remains unclear whether FAT-1 and FAT-2 desaturase expression can confer protection in mammalian in vivo models of C9orf72-associated disease. This study examined whether FAT-1– or FAT-2–mediated PUFA enrichment modulates neurodegeneration and neuroinflammation in an AAV-(G₄C₂)₁₄₉ mouse model of ALS/FTD. Western blotting, Meso Scale Discovery assays, and immunohistochemistry were used to assess neuronal density, gliosis, and dipeptide repeat pathology. Robust DPR expression was detected in 149R cohorts, but no significant neuronal loss was observed at six months. Also, a mild trend toward increased astrocytic activity was evident in 149R cohorts. FAT-2 expression was associated with subtle pathological exacerbation, including astrogliosis and reduced VAT1L neuronal density, whereas FAT-1 expression had no measurable effect on neuronal counts. These findings suggest that PUFA balance may shape inflammatory outcomes in C9orf72- mediated ALS/FTD. Future studies should employ longer disease time courses, neuron-specific regulatable expression systems, and lipidomic profiling of glial and neuronal subtypes to clarify how PUFA remodeling contributes to neurodegeneration, neuroinflammation, and ferroptosis. Confirming these mechanisms could establish lipid metabolism modulation as a promising therapeutic strategy in ALS/FTD.