Novel Targets and Treatments for Neurodegenerative Diseases Revealed by Drosophila

Neurodegenerative disorders (NDDs) such as Alzheimer's disease, Parkinson's disease, and others lack any disease-modifying therapy due to the lack of mechanistic understanding of the disease etiology. The genetic tractability, short lifespan, and conserved cellular biology of Drosophila melanogaster have positioned the fly as a powerful model organism for a pathway-driven therapeutic discovery across NDDs. Fly models expressing human pathogenic proteins, including Aβ, tau, α-synuclein, and others, recapitulate core features of these NDDs such as proteostasis defects, RNA dysregulation, mitochondrial dysfunction, lipid signaling abnormalities, and innate immune activation. Unbiased genetic and pharmacologic screens in these systems have identified conserved therapeutic nodes such as PARP signaling and insulin/IGF pathways. In this review, we discuss these advances to define conserved therapeutic axes identified in Drosophila and evaluate their translational potential for neurodegenerative disorders.