Drosophila melanogaster provides a genetically tractable and evolutionarily conserved platform for interrogating mechanisms of human neurodegeneration. This revised review critically evaluates how transgenic and genome-edited fly models expressing amyloid-beta, tau, alpha-synuclein, mutant huntingtin, and patient-relevant variants reproduce selective aspects of Alzheimer's disease, Parkinson's disease, and polyglutamine disorders, while also highlighting the boundaries of translational inference. We emphasize conserved pathogenic modules, including oxidative stress, mitochondrial dysfunction, impaired proteostasis, and stress signaling through Nrf2, JNK, and PINK1/Parkin, and distinguish robust mechanistic insights from findings that are primarily descriptive or overexpression-driven. We further discuss the specific contribution of Drosophila genetic tools such as GAL4/UAS, RNA interference, CRISPR-Cas9, and FLP/FRT-based mosaic analysis for dissecting cell-autonomous and non-cell-autonomous neurotoxicity. To improve usability, the manuscript now summarizes major disease models and natural compounds in dedicated tables, expands therapeutic discussion to include HDAC inhibitors and mitochondria/redox-directed small molecules, and outlines how fly studies can function within translational pipelines for variant interpretation, target prioritization, and preclinical triage before mammalian validation and human trials. Finally, we address key limitations of Drosophila relative to humans, including differences in metabolism, blood-brain barrier properties, immune complexity, and disease timescale, to provide a more balanced framework for using fly neurodegeneration models in precision medicine.
