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Additionally, the accumulation of aggregates slows the endocytosis pathway further, creating a negative feedback loop within the cell.
"If we genetically or chemically impede the pathway, then the TDP-43 protein accumulates and becomes super toxic. The cool thing, as far as a therapy for ALS is concerned, is that we can also do the reverse," Buchan said. "We can make the endocytosis pathway work better by over-expressing parts of it, like putting the gas pedal down so it goes really fast. When we do that, then the TDP-43 aggregates are cleared really efficiently and it's no longer toxic."
Many of the paper's experiments were performed in yeast cells, but the general findings are likely translatable to human cells based on initial findings. Buchan called yeast "a powerful genetic tool," for understanding cellular processes, including those in human disease.
While the results from Buchan's lab are unexpected - "If I were to pull a textbook off the self, it would say endocytosis is for things that are outside the cell, not inside, so it's still pretty heretical," he said - there are other labs with data suggesting endocytosis can also clear already internalized proteins.
The next step is to determine how TPD-43 and FUS enter the endocytic pathway, and then to develop ways to make endocytosis work better in these cells.
"There are genetic ways to do that, but not chemically at the moment," Buchan said. "We think if we have a drug that inhibits the negative regulators of endocytosis, the pathway will go faster as a result. We have a couple ideas of where to start next."
The findings were published in the journal Molecular and Cellular Biology . Buchan's co-authors include undergraduate Amanda Warner, former post-doctoral fellow Guangbo Liu, graduate student Aaron Byrd, former graduate student Fen Pei, assistant research scientist Eman Basha and former lab technician Allison Buchanan. Source:
University of Arizona Journal reference:
Liu, G., et al. (2020) Cdc48/VCP and Endocytosis Regulate TDP-43 and FUS Toxicity and Turnover. Molecular and Cellular Biology . doi.org/10.1128/MCB.00256-19 .
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