Columbia study suggests possible common thread between many neurodegenerative diseases | Colombia

NEW YORK — Walk around the deep cells of a brain with Alzheimer’s disease and you’ll discover tiny clumps of protein that look suspicious. Since the 1980s, when neuroscientists began to identify these protein tangles, researchers have discovered that other brain diseases have their own signature tangled proteins.

“Each of these diseases is associated with a unique protein tangle, or fibril,” said Anthony Fitzpatrick, PhD, principal investigator at the Zuckerman Institute at Columbia. “These disease-associated proteins have their own unique shapes and behaviors,” added Dr. Fitzpatrick, also an assistant professor of biochemistry and molecular biophysics at Columbia University Irving Medical Center and a member of the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain. Columbia. .

Published today in Cellresearch by Dr. Fitzpatrick and an international team of 22 collaborators reveals a new fibril in diseased brains, formed by a protein normally busy cleaning cells.

“We have a surprising and provocative result that we hope could have implications for the management of neurodegenerative diseases,” said Andrew Chang, co-first author of the paper in the Fitzpatrick lab. Drug researchers have long searched for tangle-forming proteins as targets for new drugs, but this pursuit has so far yielded largely disappointing results.

Fibril-associated diseases, some common and some rare, collectively affect millions of people worldwide. Their incidence is expected to increase as the population grows and people live longer. Unraveling what happens in these neurodegenerative diseases has a personal side to Dr. Fitzpatrick: he lost an uncle to one of them, progressive supranuclear palsy (PSP).

“We found that a protein called TMEM106B can form fibrils, and this behavior was not known before,” said Xinyu Xiang, a former member of the Fitzpatrick lab at the Zuckerman Institute and now a graduate student in the Department of Structural Biology. from Stanford University. “This protein is a central component of lysosomes and endosomes, which are organelles that clean up waste that accumulates in our cells as we age.”

Normally, TMEM106B molecules span the membranes of these waste management organelles. In a lab research feat, Fitzpatrick’s team discovered that TMEM106B molecules can split into two fragments. The fragments inside the organelles can then self-assemble into what the researchers suspect are cell-hindering fibrils.

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: PSP, dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration. (FTLD). FTLD is the most common form of dementia in people under the age of 60.

“It’s so motivating to remember that the only way we can do this research is because of the people who generously donated their brains,” said Marija Simjanoska, co-first author and one of three students at undergraduate working on the project.

Co-corresponding author Ian Mackenzie, MD, of the University of British Columbia, and co-authors Dennis Dickson, MD, and Leonard Pertrocelli, PhD, of the Mayo Clinic in Florida, helped source this valuable research resource. Join Drs. Fitzpatrick and Mackenzie as co-corresponding authors on the paper is Michael Stowell, PhD, of the University of Colorado, Boulder. The 23-member team is complemented by researchers from several other institutions, including three in Belgium.

With a world-class cryogenic electron microscope (cryo-EM), the team took snapshots of individual protein molecules from many different angles. From these, the researchers built three-dimensional models of the protein with atomic detail. These patterns, in turn, helped researchers identify TMEM106B by making educated guesses about the exact sequence of the protein’s amino acid building blocks. Just as letters form words with specific meanings, different amino acid molecules form into proteins, each with its own form and function.

Two fragments of the TMEM106B protein (blue) form a doublet by binding to a currently unidentified non-protein density (purple mesh).
(Credit: Andrew Chang and Anthony Fitzpatrick/Zuckerman Institute at Columbia University/Cell)

The researchers expected that one of the long-known fibril-forming proteins, such as tau in Alzheimer’s disease, would eventually match the patterns in the cryo-EM data. Instead, the matching exercise, which involved searching a massive database of protein sequences, yielded a stunning result.

The researchers discovered that the mysterious protein corresponded to a 135 amino acid fragment of TMEM106B. This was an exciting revelation as this same protein was identified over a decade ago in a broad hunt for genes potentially associated with FTLD.

So far, the available data only shows that TMEM106B fibrils are present in diseased brain tissue, not that the fibrils cause the diseases. Yet, Dr. Fitzpatrick points out, the prevalence of TMEM106B fibrils in tissues from different brain diseases, combined with the protein’s normal place in lysosomes and endosomes, points to a possible pathogenic role.

In their Cell article, the researchers speculate that the formation of TMEM106B fibrils disrupts the function of the lysosome, which, in turn, promotes the formation of fibrils made up of the other known fibril-forming proteins. These dysfunctions could kill brain cells, leading to dementia, movement problems, speech pathologies and other symptoms of Alzheimer’s disease, PSP, FTLD and other brain diseases with protein tangles revealers.

“We now have a promising new lead,” said Dr. Fitzpatrick. “This could point to a common thread connecting a range of neurodegenerative diseases and could pave the way for new interventions.”


the Cell the article is titled “Homotypic fibrillation of TMEM106B in various neurodegenerative diseases”

The authors of the article are Andrew Chang, Xinyu Xiang, Jing Wang, Carolyn Lee, Tamta Arakhamia, Mrija Simjanoska, Chi Wang, Yari Carlomagno, Guoan Zhang, Shikhar Dhingra, Manon Thierry, Jolien Perneel, Bavo Heeman, Lauren M. Forgrave , Michael DeTure, Mari L. DeMarco, Casey N. Cook, Rosa Rademakers, Dennis Dickson, Leonard Petrucelli, Michael HB Stowell and Ian RA Mackenzie and Anthony Fitzpatrick.

The authors declare no competing interests.

This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorder and Stroke (UO1NS110438, U54NS110435); the Frontotemporal Degeneration Association; Canadian Institutes of Health Research (74580); and the MCDB Neurodegenerative Disease Fund.

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