Possible common thread between many neurodegenerative diseases
Discovery reveals that a protein normally involved in clearing cells of molecular debris can clump into fibrils, potentially hobbling cells

Date:
March 4, 2022
Source:
Columbia University
Summary:
Researchers reveal a new fibril in diseased brains, one formed by
a protein normally busy cleaning cells.



FULL STORY ==========================================================================
Take a cell-deep tour of a brain afflicted with Alzheimer's disease,
and you will find minuscule clumps of protein that seem suspicious. Ever
since the 1980s, when neuroscientists began identifying these protein
tangles, researchers have discovered that other brain diseases have
their own tangled- protein signatures.


========================================================================== "Each of these diseases has a unique protein tangle, or fibril, associated
with it," said Anthony Fitzpatrick, PhD, principal investigator
at Columbia's Zuckerman Institute. "These proteins associated with
diseases have their own 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 Columbia's
Taub Institute for Research on Alzheimer's Disease and the Aging Brain.

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

"We have a surprising and provocative result that we hope could have
some bearing on managing neurodegenerative diseases," said undergraduate
Andrew Chang, a co-first author on the paper in the Fitzpatrick lab. Drug researchers have long pursued the tangle-forming proteins as targets for
new medicines, but this pursuit so far has largely delivered disappointing results.

Fibril-associated diseases, some common and some rare, collectively
affect millions of people around the world. Their incidence is slated
to increase as the population grows and people live longer. Untangling
what is going on in these neurodegenerative diseases has a personal
facet for Dr. Fitzpatrick: He lost an uncle to one of them, progressive supranuclear palsy (PSP).

"We have found that a protein called TMEM106B can form fibrils,
and this behavior was not known before," said Xinyu Xiang, formerly
a member of the Fitzpatrick lab at the Zuckerman Institute and now
a graduate student at Stanford University's Department of Structural
Biology. "This protein is a core component of lysosomes and endosomes,
which are organelles that clean up the junk that builds up in our cells
as we get older." Normally, TMEM106B molecules span the membranes of
those waste-management organelles. In a feat of laboratory sleuthing, Fitzpatrick's team discovered that TMEM106B molecules can split into
two fragments. Fragments inside the organelles can then self-assemble
into what the researchers suspect could be cell-hobbling fibrils.



==========================================================================
To make this discovery, the researchers first extracted proteins
from brain tissue donated by 11 patients who had died from three neurodegenerative diseases associated with misfolded proteins: PSP,
dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration
(FTLD). FTLD is the most prevalent form of dementia for those under 60
years of age.

"It's so motivating to remember that the only way we can do this research
is because of people who generously donated their brains," said Marija Simjanoska, a co-first author and one of the three undergraduates 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 procure this precious research resource.

Joining Drs. Fitzpatrick and Mackenzie as co-corresponding authors
on the paper is Michael Stowell, PhD, of the University of Colorado,
Boulder. Filling out the 23-member team are 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 at many different angles. From
these, the researchers constructed three-dimensional models of the
protein in atomic detail. Those models, in turn, helped the researchers identify TMEM106B by making educated guesses about the exact sequence of
the protein's amino-acid building blocks. Much in the way letters string
into words with specific meanings, different amino-acid molecules build
into proteins, each with its own shape and function.

The researchers fully expected that one of the long-known fibril-forming proteins, such as the tau protein in Alzheimer's disease, would end up
matching with the models from the cryo-EM data. Instead, the matching
exercise, which involved searching in a massive database of protein
sequences, delivered a head-turning result.



==========================================================================
The researchers found that the mysterious protein matched a 135-amino-acid fragment of TMEM106B. That was an exciting revelation because this same
protein was identified more than a decade ago in a broad hunt for genes potentially associated with FTLD.

So far, the data in hand shows only that TMEM106B fibrils are present in diseased brain tissue, not that the fibrils cause the diseases. Still, Dr.

Fitzpatrick points out, the prevalence of TMEM106B fibrils in tissue
from different brain diseases, combined with the protein's normal place
in lysosomes and endosomes, points toward a possible disease-causing role.

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

"We now have a promising new lead," said Dr. Fitzpatrick. "It could point towards a common thread linking a range of neurodegenerative diseases and
could open the way to new interventions." This work was supported by the National Institutes of Health (NIH)/National Institute of Neurological
Disorder and Stroke (UO1NS110438, U54NS110435); the Association for Frontotemporal Degeneration; Canadian Institutes of Health Research
(74580); and MCDB Neurodegenerative Disease Fund.


========================================================================== Story Source: Materials provided by Columbia_University. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Andrew Chang, Xinyu Xiang, Jing Wang, Carolyn Lee, Tamta Arakhamia,
Marija 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 W. Dickson, Leonard
Petrucelli, Michael H.B. Stowell, Ian R.A. Mackenzie, Anthony
W.P. Fitzpatrick. Homotypic fibrillization of TMEM106B across
diverse neurodegenerative diseases. Cell, 2022; DOI: 10.1016/
j.cell.2022.02.026 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220304182948.htm

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