Sometimes called the cellular recycling system, lysosomes are tiny structures that break down and clear away molecular waste to keep cells young and fresh. For this reason, they have been implicated in many age-related diseases such as cancer, Alzheimer’s and Parkinson’s, but a new understanding of the way these organelles repair themselves could lead to new ways to stop such conditions in their tracks.
“Lysosome damage is a hallmark of aging and many diseases, particularly neurodegenerative disorders such as Alzheimer’s,” said lead author Jay Xiaojun Tan from the University of Pittsburgh. “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.”
Key to the function of lysosomes is a membrane that serves the important purpose of containing the powerful digestive enzymes they use to eat up molecular waste. By walling these enzymes off, the membrane keeps the rest of the cell healthy and in tact. This membrane can spring leaks, but healthy cells are able to promptly plug the gaps and restore the lysosome to full function.
Tan and his team sought to understand the processes underpinning this repair process, by observing damaged lysosomes in lab-grown cells. The scientists watched on as proteins descended on the injured organelles, and one in particular caught their eye. The enzyme called PI4K2A promptly arrived and generated large amounts of a signaling molecule called PtdIns4P.
“PtdIns4P is like a red flag,'” said Tan. “It tells the cell, ‘Hey, we have a problem here.’ This alert system then recruits another group of proteins called ORPs.”
The ORPS were then found to work like tethers, hooking up to the lysosomes PtdIns4P at one end and a cellular structure called the endoplasmic reticulum at the other. This structure plays a role in the synthesis of proteins and lipids, and it was found to create cholesterol and a lipid called phosphatidylserine, which patch up holes in the membrane and are key to whole lysosome repair process.
Phosphatidylserine was also found to activate another protein called ATG2, which helps transport lipids to the lysosome in a final step of the repair process. In follow-up experiments, the team deleted the gene that encodes for the PI4K2A enzyme and found that tau fibrils linked to Alzheimer’s disease were allowed to grow freely.
The scientists believe that in young and healthy people, the lysosomes are quickly repaired through this pathway, but aging and disease can compromise its function causing leaky lysosomes to accumulate, accelerating aging and the onset of some diseases. Among the next steps for the scientists are experiments exploring how the pathway can be leveraged to protect mice from developing Alzheimer’s.
“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 senior author Toren Finkel. “I believe these findings are going to have many implications for normal aging and for age-related diseases.”
The research was published in the journal Nature.
Source: University of Pittsburgh via Phys.org
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