Researchers identify DIP-β as a glial regulator of brain aging and lifespan in Drosophila

A Drosophila study utilizing in-situ cell-surface proteomics has identified the synaptic wiring protein DIP-β as a potential glial regulator of brain aging, demonstrating that adult glial overexpression of the molecule extends lifespan and preserves motor function.

Researchers applied a modified peroxidase-mediated proximity-based biotinylation procedure in-situ to profile the glial cell-surface proteomes of intact central brains in young (5 days) and old (50 days) Drosophila.

Out of 2,007 proteins detected with two or more unique peptides, ratiometric and cutoff analyses identified 872 glial cell-surface and extracellular matrix proteins, with 127 unique to young flies, 216 unique to old flies, and 529 found in both.

Gene Ontology and protein-protein interaction analyses showed that aging-induced downregulated proteins were primarily associated with neural development, synaptic wiring, and cell adhesion, whereas upregulated proteins related to cell localization, transport, and homeostasis.

A genetic screen of 48 candidate cell-surface or extracellular genes identified DIP-β (a synapse wiring molecule downregulated in aged brains) as a promising pro-longevity factor.

Overexpressing DIP-β in adult glial cells (using the drug-inducible GeneSwitch system) significantly extended lifespan in both male and female flies and improved motor control (climbing ability) in aged flies.

Single-nucleus RNA sequencing of 48,959 high-quality cells from fly heads revealed that DIP-β overexpression mainly altered the transcriptomes of cortex glia, ensheathing glia, and fat cells, showing improved glia-neuron and glia-fat cell communication via TGF-beta, Wnt, FGFR, and EGFR pathways.

Traditional proteomics platforms using biochemical fractionation struggle to preserve cell-type specificity and often omit crucial secreted and extracellular matrix proteins that facilitate glia-neuron interactions.

This study represents the first application of in-situ cell-surface proteomics to glial cells in intact brains to capture the native physical relationships of glia-neuron junctions during the aging process.

It establishes a functional role for immunoglobulin superfamily cell adhesion molecules (specifically the DIP/Dpr heterophilic binding partners) in the aging brain, suggesting that overexpressing key wiring molecules in glia can compensate for the global decline of synaptic connectivity and structural integrity associated with normal brain aging and age-related neurodegeneration.

Provides a robust proof-of-concept workflow for target discovery using spatially resolved, in-situ proteomics, potentially accelerating the identification of novel, cell-surface-accessible therapeutic targets for neurodegenerative diseases.

Expands the landscape of aging-related target discovery beyond classical intracellular pathways (such as autophagy or mitochondrial dysfunction) into the structural biology of the extracellular matrix and synaptic adhesion networks.

Translational verification to determine if orthologs of DIP-β (such as the human IgLON family member IgLON5) or their downstream pathways play a similar protective role in mammalian models of brain aging and neurodegeneration.