Unexpected Protein Implicated in Brain Disorder

Researchers in California have found that the amyloid fibrils associated with frontotemporal lobar degeneration (FTLD)—the third most common neurodegenerative disorder after Alzheimer’s and  Parkinson’s—were composed of an unexpected protein.

The findings, published recently in Nature, may lead to new therapeutic targets for the disease, which damages the brain’s frontal and temporal lobes. It 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, FTLD-TDP,  is characterized molecularly by dense, spherical aggregates in brain cells made up of the protein TDP-43. For this reason, the team at University of California–Los Angeles was surprised to find the amyloid fibrils in FTLD were comprised of TMEM106B instead.

The discovery came after UCLA molecular biology graduate student Yi Xiao (Sean) Jiang and UCLA postdoctoral fellow Qin Cao were 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. Using cryogenic electron microscopy (cryo-EM) Jiang, Cao, and 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, says UCLA professor David Eisenberg.  

In a 2005 paper also published in Nature, Eisenberg and an international team of chemists and molecular biologists reported that these are made up of proteins that interlock like the teeth of a zipper. But TMEM106B forms multiple molecular zippers, making FTLD fibrils more complex than the pathogenic fibrils seen in Alzheimer’s and Parkinson’s.  Like other fibrils, they are made of stacks of thousands of layers, each formed by single protein molecules with straight segments and bent corners, folding into a complex shape. But in TMEM106B, the folded protein chain has 18 straight segments, which the researchers liken to the 18 fairways of a golf course because 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,” adds Eisenberg. “Further research may also discover a connection between the actions of TMEM106B and TDP-43. It’s too early to tell.” At the very least, he says, the most recent paper will alert researchers studying neurodegeneration that a new protein may potentially play a role, he adds.