Microglia are brain-resident macrophages that clear extracellular debris, such as apoptotic cells and protein aggregates. This task relies on a functional endolysosomal system, and dysregulation of microglial lysosomal activity is implicated in neurodegenerative diseases, such as Alzheimer’s disease, which is characterised by the accumulation of amyloid-β aggregates. ClC7, a chloride–proton antiporter, is localised to endolysosomal compartments and has been extensively studied in neurons; however, its function in microglia in vivo is largely unknown. Now, in this Short Report (Iyer and Talbot, 2024), the authors show that microglia with mutations in clcn7, which encodes the ClC7 protein, cause reduced processing of endogenous debris in zebrafish embryos. Furthermore, ClC7-deficient microglia and macrophages are unable to effectively process exogenous debris injected into larvae, such as E. coli or amyloid-β fibrils. Interestingly, however, microglia number and morphology are unaffected in both heterozygous and homozygous clcn7 mutant larvae. Similarly, late endosomes and lysosomes appear unchanged, despite the accumulation of debris in these compartments. A mutation in ostm1, the β-subunit of ClC7, also leads to a phenotype that is similar to that of clcn7. Together, these findings suggest that ClC7 is required for a functional endolysosomal system and highlight the importance of ClC7 in microglial clearance of extracellular debris in vivo.
