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Take a cell-deep tour of the brains of Alzheimer's patients and you'll find tiny clumps of proteins that seem suspicious
"Each disease has unique protein tangles or fibers associated with it," said lead researcher Anthony Fitzpatrick, Ph.
Published today in the journal Cell, Dr Fitzpatrick and an international team of 22 collaborators revealed a new fibre in the diseased brain that is produced by a Usually busy cleaning cells from protein formation
"We have a surprising and exciting result that we hope will have some implications for the treatment of neurodegenerative diseases," said undergraduate student Andrew Chang, co-first author of the paper in Fitzpatrick's lab
Fibrin-related disorders, some common and some rare, collectively affect millions of people around the world
"We've discovered that a protein called TMEM106B can form fibers, a behavior that wasn't known before," said Xinyu Xiang, a former member of the Fitzpatrick lab at the Zuckerman Institute and now a graduate student in Stanford's Department of Structural Biology.
Typically, TMEM106B molecules span the membranes of these waste-processing organelles
To make this discovery, the researchers first extracted proteins from brain tissue donated by 11 patients who died of three neurodegenerative diseases associated with misfolded proteins
"The only way we can do this research is by people who have generously donated their brains, which is very exciting," said Marija simjanosska, one of the project's first authors and three undergraduate students involved in the project one
Co-corresponding authors Ian Mackenzie, MD, of the University of British Columbia, and co-authors Dennis Dickson, MD, and Leonard Pertrocelli, MD, of the Mayo Clinic in Florida, helped access this valuable research resource
Using a world-class cryo-electron microscope (Cryoo-EM), the team took snapshots of individual protein molecules from many different angles
The researchers fully anticipated that a long-known fibrogenic protein, such as the tau protein in Alzheimer's, would eventually match the model in the cryo-electron microscopy data
The researchers found that this mysterious protein matched a 135-amino acid fragment of TMEM106B
The data at hand so far only suggest that TMEM106B fibrils are present in diseased brain tissue, not that fibrils cause disease
In their Cell paper, the researchers speculate that TMEM106B fibril formation disrupts lysosome function, which in turn promotes the formation of fibrils composed of other known fibril-forming proteins
"We now have a promising new lead," Dr.
Fitzpatrick said
.
"This could point to common threads between a range of neurodegenerative diseases and could open the way for new interventions
.
"
