Unexpected protein could play role in common brain disorder
Date:
April 20, 2022
Source:
University of California - Los Angeles
Summary:
Scientists report that amyloid fibrils found in people with
frontotemporal degeneration contain the little-known protein
TMEM106B.
FULL STORY ========================================================================== Scientists have known for years that amyloid fibrils -- fibrous, ropelike structures formed by closely linked protein molecules -- are present
in the brains of patients with Alzheimer's and Parkinson's diseases and
likely play a role in the progression of these disorders.
==========================================================================
Now, UCLA biochemists have discovered such fibrils in the brains of
people with a form of frontotemporal lobar degeneration, or FTLD,
the most common neurodegenerative disorder after Alzheimer's and
Parkinson's. But surprisingly, the type of protein they expected to
find in these potentially harmful fibrils wasn't there at all; instead,
a little-known protein called TMEM106B was identified as the culprit.
The findings, published in the journal Nature, are likely to lead
to a new focus on TMEM106B in FTLD and similar brain diseases, the
researchers said.
FTLD, which involves damage to the brain's frontal and temporal lobes,
strikes people earlier in life than Alzheimer's and Parkinson's,
causing dementia in 80 out of 100,000 people between the ages of 45
and 64. Symptoms can include acute changes in behavior and a decline in language skills. The form of the disease studied by the researchers is characterized molecularly by dense, spherical aggregates in brain cells,
which are made up of the protein TDP-43.
The UCLA team presumed that if there were amyloid fibrils in the brains
of people with FTLD, these fibrils would be composed of TDP-43.
The study's lead authors, UCLA molecular biology graduate student Yi
Xiao (Sean) Jiang and UCLA postdoctoral fellow Qin Cao, both working
in laboratory of UCLA professor David Eisenberg, were indeed able to
extract amyloid fibrils from frozen brain tissues provided by the Mayo
Clinic from four deceased patients who had been diagnosed with FTLD-TDP.
========================================================================== However, using a technique called cryogenic electron microscopy,
or cryo-EM - - which allowed them to image large biomolecules in
extraordinary detail - - they, along with UCLA bioinformatics researcher Michael Sawaya, determined that the fibrils were composed solely of
TMEM106B, or transmembrane protein 106B.
Not much is known about TMEM106B, although genetic scientists found
evidence a decade ago that a mutation of the protein is a risk factor
for FTLD, said senior author Eisenberg, the Paul D. Boyer Professor
of Molecular Biology at UCLA and a Howard Hughes Medical Institute investigator.
Like a golf course: The structure of amyloid fibrils in FTLD Pathological deposits of amyloid proteins are associated with more than 50 degenerative
and potentially fatal diseases, according to Eisenberg, who has studied
amyloid fibrils for years.
In a 2005 Naturepaper, Eisenberg and an international team of chemists
and molecular biologists reported that these fibrils are made up of
proteins that interlock like the teeth of a zipper -- an observation that
has been supported by recent studies. TMEM106B, he said, forms multiple molecular zippers.
==========================================================================
The team's structural analysis of TMEM106B fibrils shows that they share features with the pathogenic fibrils seen in Alzheimer's and Parkinson's
but are more complex, Eisenberg noted. Like those other fibrils, they
are made of stacks of thousands of layers, each layer formed by single
protein molecules with straight segments and bent corners, folding into
a complex shape.
In TMEM106B, the folded protein chain has 18 straight segments, which
the researchers liken to the 18 fairways of a golf course -- and like
a golf course, the first and 18th fairways are near each other. "So we
say TMEM106B has a golf course-like fold," Eisenberg said.
Whether the TMEM106B amyloid fibrils contribute to causing FTLD-TDP
remains to be seen. It is also unclear what, if any, role may be played by
the TDP-43 proteins, whose normal function is to shepherd RNA molecules carrying DNA blueprints for proteins from the nucleus of brain cells to
the cytoplasm.
"TMEM106B may be found to be a cause of FTLD. In that case, our knowledge
of the structure will aid in the design of therapeutics," Eisenberg
said. "Further research may also discover a connection between the
actions of TMEM106B and TDP-43. It's too early to tell.
"But at the least, the present paper will alert the community of
researchers studying neurodegeneration that a new protein may potentially
play a role," he said.
UCLA co-authors of the paper are Romany Abskharon, Peng Ge, Janine Fu,
Rachel Ogorzalek and Joseph Loo. Michael DeTure and Dennis Dickson of
the Mayo Clinic in Jacksonville, Florida, provided patient tissues and contributed neuropathological analyses.
Lead author Cao now heads his own lab at China's Shanghai Jiao Tong
University.
Funding sources included the National Institute on Aging, part of the
National Institutes of Health, and the Howard Hughes Medical Institute.
========================================================================== Story Source: Materials provided by
University_of_California_-_Los_Angeles. Original written by Stuart
Wolpert. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Yi Xiao Jiang, Qin Cao, Michael R. Sawaya, Romany Abskharon,
Peng Ge,
Michael DeTure, Dennis W. Dickson, Janine Y. Fu, Rachel R. Ogorzalek
Loo, Joseph A. Loo, David S. Eisenberg. Amyloid fibrils in disease
FTLD-TDP are composed of TMEM106B not TDP-43. Nature, 2022; DOI:
10.1038/s41586- 022-04670-9 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220420092156.htm
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