Unexpected protein may be messing with your brain

Scientists have known for years that amyloid fibrils -- fibrous rope-like structures formed from tightly linked protein molecules -- are present in the brains of people with Alzheimer's and Parkinson's and may play a role in the development of these diseases

Now, UCLA biochemists have identified such fibrils in the brains of people with frontotemporal lobe degeneration (FTLD)

The findings, published in the journal Nature, may spark new attention to TMEM106B in FTLD and similar brain diseases, the researchers said

Damage to the frontal and temporal lobes of the brain in FTLD occurs earlier than Alzheimer's and Parkinson's, and affects 80 out of every 100,000 people aged 45 to 64 with dementia

The UCLA team speculates that if amyloid fibrils were present in the brains of FTLD patients, those fibrils would consist of TDP-43

Amyloid fibrils were extracted from frozen brain tissue of four deceased patients diagnosed with FTLD-TDP

However, using a technique called cryo-electron microscopy, or cryo-electron microscopy, they can image large biomolecules in great detail, and together with UCLA bioinformatics researcher Michael Savaya, they determined that these fibrils Consists only of TMEM106B or transmembrane protein 106B

Even though genetic scientists discovered a decade ago that mutations in this protein were a risk factor for FTLD, senior author Paul Boyle Professor of Molecular Biology at UCLA and Howard Hughes Medical Institute investigator Eisenberg said evidence, but little is known about TMEM106B

Like a golf course: the structure of amyloid fibrils in FTLD

According to Eisenberg, who has studied amyloid fibrils for many years, pathological deposits of amyloid have been linked to more than 50 degenerative and potentially fatal diseases

In a 2005 paper in the journal Nature, Eisenberg and an international team of chemists and molecular biologists reported that these fibers are made of proteins that act like the teeth of a zipper occlusal - recent research has supported this observation

Eisenberg noted that the team's structural analysis of TMEM106B fibrils showed that they share the same characteristics as the causative fibrils of Alzheimer's and Parkinson's disease, but are more complex

In TMEM106B, the folded protein chain has 18 straight segments, which the researchers likened to the 18 fairways of a golf course -- just like a golf course, where the first and 18th fairways are close to each other

Whether TMEM106B amyloid fibrils lead to FTLD-TDP remains to be seen

"TMEM106B may be one of the causes of FTLD
.
In this case, our knowledge of the structure will help in the design of therapeutics," Eisenberg said
.
"Further studies may also identify TMEM106B and TDP- 43 links between behaviors
.
It is too early to draw conclusions
.

"But at the very least, this paper will remind researchers studying neurodegeneration that a new protein may play a potential role," he said
.

Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B not TDP-43