Cell Signaling Pathway Repairs Damaged Lysosomes

While lysosomes are involved in many vital functions, such as removing cellular debris, researchers have been increasingly investigating their role in healthy and abnormal aging. With certain neurodegenerative diseases like Alzheimer’s, lysosomes become damaged and “leaky,” which is particularly dangerous due to their harmful contents. To learn more about these mechanisms, a research team from the University of Pittsburgh identified a pathway by which cells were able to repair damaged lysosomes.

“Lysosome damage is a hallmark of aging and many diseases, particularly neurodegenerative disorders such as Alzheimer’s,” says first author Jay Xiaojun Tan, Ph.D., assistant professor of cell biology at Pitt’s School of Medicine. “Our study identifies a series of steps that we believe is a universal mechanism for lysosomal repair, which we named the PITT pathway as a nod to the University of Pittsburgh.” 

Since lysosomes are primarily responsible for the safe removal of cell waste, having damaged membranes introduces a unique set of challenges within the extracellular space. They can often contain digestive enzymes that can degrade other parts of the cell. In Alzheimer’s, leakage of tau fibrils from damaged lysosomes is a crucial step in disease progression. While a healthy cell can repair most harm, this is not always the case in diseased states or weakened immune systems.

To begin, the team experimentally damaged lysosomes from lab-grown cells and analyzed the resulting proteins. They found that an enzyme called PI4K2A accumulated within the lysosomes minutes after damage had occurred and produced high levels of a signaling molecule called PtdIns4P.

“PtdIns4P is like a red flag. It tells the cell, ‘Hey, we have a problem here,’” said Tan. “This alert system then recruits another group of proteins called ORPs.”

Tan elaborates that the ORP proteins act as “tethers,” where one end binds to the PtdIns4P flag on the lysosome, and the other attaches to the endoplasmic reticulum. “The endoplasmic reticulum wraps around the lysosome like a blanket,” states co-author Toren Finkel, M.D., Ph.D., director of the Aging Institute and distinguished professor of medicine at Pitt’s School of Medicine. “Normally, the endoplasmic reticulum and lysosomes barely touch each other, but once the lysosome was damaged, we found that they were embracing.”

Then, cholesterol and phosphatidylserine can be injected into the lysosome to patch up holes in the membrane. Phosphatidylserine also activates a protein called ATG2, which assists in transferring additional lipids to the lysosome for membrane repair. The authors dubbed this entire pathway as the PITT, or phosphoinositide-initiated membrane tethering and lipid transport, pathway.

“What’s beautiful about this system is that all of the components of the PITT pathway were known to exist, but they weren’t known to interact in this sequence or for the function of lysosome repair,” said Finkel. “I believe these findings are going to have many implications for normal aging and for age-related diseases.”

Notably, Tan deleted the gene encoding the PI4K2A enzyme, which was the first noted in the PITT pathway. After it was removed, he found that tau fibril spreading dramatically increased, suggesting that defects within this form of cell signaling could contribute to Alzheimer's disease progression. For future work, the team wants to develop mouse models to further understand whether the PITT pathway can protect mice from developing Alzheimer's disease.

Their findings were published in the journal Nature.