Take a cell-deep tour of a brain afflicted with Alzheimers disease, and discover minuscule clumps of protein that seem suspicious. In the 1980s, when neuroscientists began identifying these protein tangles, researchers have discovered that other brain illnesses have their own tangled-protein signatures.
According to anthony Fitzpatrick, PhD, a principal investigator at the Columbias Zuckerman Institute. These proteins involved in diseases have their own patterns and behaviors, according to Dr. Fitzpatrick, who is also an assistant professor of biochemistry and molecular biophysics at the Columbia University Irving Medical Center and a member of the Columbias Taub Institute for Research on Alzheimers Disease and the Aging Brain.
A new fibril in diseased brains has been discovered, according to Dr. Fitzpatrick and an international team of 22 researchers. One protein formed by a normally busy cleaning cell is found in the research.
According to Andrew Chang, a co-author on the paper in theFitzpatrick lab, we have a surprising and provocative outcome that we hope will have a positive impact on management of neurodegenerative diseases. Drug specialists have long considered the tangled proteins as targets for new medicines, but this pursuit has thus far largely led disappointing results.
Fibril-associated illnesses, some common and some rare, have devastating effects on millions of people around the globe. Their incidence is expected to increase as the population grows and people live longer. Dr. Fitzpatrick has a personal facet: he lost an uncle to one of them, a progressive supranuclear palsy.
According to Xinyu Xiang, a member of the Zuckerman Institute and now a graduate student of the Stanford University Department of Structural Biology. This protein is one of the most crucial components of lysosomes and endosomes, which is organelles that clean up the decay that builds up in our cells as we age.
TMEM106B molecules extend the membranes of those waste-management organelles in a simple manner. Fitzpatricks team discovered that TMEM106B molecules can be divided into two sections. Fragments inside the organelles can then self-assemble into what they suspect could be cell-hobbling fibrils.
Proteins were first extracted from brain tissue from 11 patients who had died of three neurodegenerative diseases linked to misfolded proteins: PSP, dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration (FTLD). This is the most prevalent form of dementia for people under 60 years of age.
It''s so important to remember that the only way we can do this research is through generous donation of their brains, according to Marija Simjanoska, a co-first author and one of the three undergraduates working on the project.
Michael Stowell, PhD, of the University of Colorado, Boulder, is being assisted by co-authors, including Ian Mackenzie, MD, and Dennis Dickson, MD, and Leonard Pertrocelli, PhD, of the Mayo Clinic in Florida. Among the three members of the 23-member team, researchers from several other institutions, including three in Belgium.
Using a world-class cryogenic electron microscope (cryo-EM), the team took pictures of individual protein molecules at many different angles. Upon examination, the researchers discovered three-dimensional representations of the protein in atomic detail. These findings, in turn, helped researchers identify TMEM106B by making educated guesses about the exact sequence of amino-acid building blocks. Many in the way letters string into words with specific meanings, different amino-acid molecules form into proteins, each with its own shape and
The researchers believed that one of the previously-known fibril-forming proteins, such as the tau protein in Alzheimers disease, would end up matching with the cryo-EM models. Instead, the matching exercise, which involved researching a massive database of protein sequences, yielded a head-turning result.
The researchers discovered that the mysterious protein corresponded to a 135-amino-acid sample of TMEM106B. That was an interesting revelation because this same protein was identified more than a decade agoin a broad search for genes that might be linked with the FTLD.
So far, the data in hand shows only that TMEM106B fibrils are present in diseased brain tissue rather than that the fibrils cause the diseases. Yet, Dr. Fitzpatrick believes that the prevalence of TMEM106B fibrils in tissue from different brain diseases, combined with the proteins that have their standard effect in lysosomes and endosomes, leads to a possible disease-causing role.
The scientists in theirCellpaper believe the formation of TMEM106B fibrils disrupts the lysosome function, which in turn increases the formation of fibrils made of other known fibril-forming proteins. These shortcomings may cause brain cells to die, as well as dementia, movement problems, speech pathologies, and other symptoms of Alzheimers, PSP, and FTLD, as well as other brain diseases.
Dr. Fitzpatrick believes this step is important. It might lead to a common thread linking a range of neurodegenerative diseases and could lead to more interventions.