Drosophila Appl Loss Disrupts Mitochondrial, Oxidative, and Glycosylation Pathways Conserved in Alzheimer’s Disease

ABSTRACT: The physiological functions of the Amyloid Precursor Protein (APP) remain unclear due to genetic redundancy and complex phenotypes. For decades, Drosophila Amyloid Precursor Protein-Like (Appl) research has relied on APPLd, a presumed null allele generated by irradiation. Here, we show that APPLd contains complex chromosomal rearrangements and background mutations confounding the interpretation of gene function. To address this, we created a precise CRISPR toolkit, including clean null and reporter alleles. Deep proteomic profiling reveals that true Appl loss affects N-linked glycosylation, mitochondrial, and metabolic functions in a distinct signature from the background of APPLd. This conserved metabolic signature mirrors alterations in human patients and mouse Alzheimer’s models and is associated with disrupted sleep and locomotion in flies. Our findings correct the genetic understanding of Appl, establishing it as a conserved regulator of metabolic balance essential for neuronal function.

INSTRUMENT(S):

ORGANISM(S): Drosophila Melanogaster (fruit Fly)

DISEASE(S): Alzheimer's Disease

SUBMITTER: Conor Jenkins  

LAB HEAD: Fernando J. Vonhoff

PROVIDER: PXD073417 | Pride | 2026-10-15

REPOSITORIES: Pride