Krabbe Disease
https://www.cell.com/molecular-cell/abstract/S1097-2765(25)00201-1
Lysosomes are vital components of our cells that act like recycling centres to break down and reuse cellular waste. When lysosomes are damaged or not working properly, toxic materials can build up, resulting in a group of rare but serious conditions known as lysosomal storage disorders (LSDs), many of which affect the brain and nervous system. This study uncovers an unexpected role for a protein called STING (stimulator of interferon genes), which is usually known for activating the immune system in response to infections. The researchers discovered that STING also supports lysosomal health by helping cells detect and ‘bounce-back’ from lysosomal damage. It was found that in both cell experiments and mouse models of LSDs, STING activates a key regulator known as TFEB. TFEB controls the production of lysosomal and autophagy-related genes, helping cells rebuild damaged lysosomes. Additionally, this function of STING relies on its proton channel activity, a part of the protein that helps move protons across membranes and is separate from its immune signalling role. Blocking STING’s proton channel prevented the activation of TFEB and reduced the cell’s ability to repair lysosomes. On the other hand, STING can drive neuroinflammation when lysosomes become damaged as there are multiple functional regions in the STING protein cell membrane. This encouraged researchers to look further into which region might be responsible for lysosomal generation, which was found to be the transmembrane region. The findings of this study reveal that STING acts as a kind of quality control sensor for lysosomes, helping the cell respond to stress and restore normal function. Understanding the dual role of STING could lead to therapies that enhance lysosomal repair while avoiding harmful inflammation, offering hope for better treatments in LSDs and related neurodegenerative conditions.