Objective: Establishing a FAHN Drosophila model to identify cellular disease mechanisms.

Background: Fatty acid hydroxylase-associated neurodegeneration (FAHN) is an early-onset neurodegenerative disease that manifests brain abnormalities and motor dysfunction. FAHN is caused by biallelic mutations of fatty acid 2-hydroxylase (FA2H), whose encoded protein is involved in the hydroxylation of 2-hydroxyceramide and thus related to the sphingolipid metabolism. Only few FAHN model organisms have been developed to date, providing first insights into symptomatic effects. However, the underlying cellular mechanism of FAHN has not yet been elucidated. Drosophila Melanogaster is a powerful model organism that has provided important insights into many neurodegenerative diseases, and so far, no Drosophila FAHN model has been established.

Method: We characterized a FAHN fly model by examining three different loss-of dfa2h flies for motor dysfunction and longevity. Furthermore, immunofluorescence microscopy using a mitochondrial and an autophagy marker was performed with larval muscle cells and patient-derived fibroblasts to validate if cellular abnormalities are evolutionarily conserved and relevant for the disease pathogenesis.

Results: Loss of dfa2h flies had a shortened lifespan and showed behavioral abnormalities such as motor dysfunction and the inability to fly. Moreover, cellular analyses revealed alterations in mitochondrial morphology and autophagy. Analyses of patient-derived fibroblasts revealed similar results, indicating evolutionary conservation of the cellular abnormalities and their relevance in the disease context.

Conclusion: We present a promising FAHN Drosophila model that provides first insights into the cellular consequences of FA2H loss.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mitochondrial-and-autophagy-alteration-in-a-new-fatty-acid-hydroxylase-associated-neurodegeneration-fahn-model/