26 Nov 2024

Cryo-EM has solved yet another molecular riddle. In the September 6 Acta Neuropathologica, scientists led by Bernardino Ghetti, Indiana University School of Medicine, Indianapolis, reported that Biondi bodies—protein inclusions in ependymal cells of the central nervous system—comprise fibrils of none other than TMEM106b. In Biondi bodies, the transmembrane protein contorts itself much the same way as it does in TMEM106b fibrils found in the brain parenchyma of healthy older people or in those with various neurodegenerative diseases.

Peter Nelson, a neuropathologist at the University of Kentucky, Lexington, told Alzforum that he has seen the same thing in brain samples. “It is a very real phenomenon,” he wrote.

The ependymal cells that harbor these ring-like bodies line the choroid plexus, brain ventricles, and spinal canal. They filter blood and help produce and pump cerebrospinal fluid. “How these inclusions impact CSF production is unknown,” Ghetti told Alzforum.   

Biondi bodies were first described more than 100 years ago by the Spanish neuroscientists Pio del Rio Hortega, a contemporary of Santiago Ramón y Cajal, and later by Giosné Biondi (del Rio Hortega, 1918; Biondi G, 1933). More recently, thanks to electron microscopy, scientists saw that these inclusions contained filaments 10 to15 nm in diameter, but what these argyrophilic structures were made of remained a mystery.

To find out, first author Ghetti examined brain samples from 1,126 people that had been stained with Thioflavin S as part of a neuropathological workup. Of these, 1,005 contained Biondi bodies. More than 500 of their donors had been diagnosed with Alzheimer’s disease, almost 160 had had some form of frontotemporal dementia, 137 diffuse Lewy body disease, while others had died with ALS, prion disease or, in 134 cases, no clear diagnosis.

There was no correlation between diagnosis and the presence of Biondi bodies. There was for age, however. People whose brain had had these inclusions had grown considerably older than those without.

TMEM106b Amyloid. In the choroid plexus, cells labelled with the TMEM239 antibody (red) also bind the amyloid dye pFTAA (green). Right panel shows merge. [Courtesy of Ghetti et al., 2024.]

So, what is the stuff of Biondi bodies? Since TMEM106b fibrils have been found in the parenchyma not only of people with various neurodegenerative diseases but also of healthy older folks, Ghetti wondered whether it might be involved. He labeled tissue samples with TMEM239, an antibody previously raised against TMEM106b in the lab of co-author Michel Goedert at the Medical Research Council Laboratory of Molecular Biology at the University of Cambridge, U.K. (Schweighauser et al., 2022). Biondi bodies in ependymal cells of choroid plexuses, cerebral ventricles, and spinal cord canal all bound avidly, and they co-stained for the amyloid dye pFTAA (image above). They did not bind antibodies to other amyloidogenic proteins, including tau, Aβ, TDP-43, and α-synuclein.

Further evidence that the fibrils comprised TMEM106b came from electron microscopy. Biondi bodies fibrils bound gold-conjugated secondary antibodies to TMEM239 (image below).

Behold the Body. Electron microgram of a Biondi body shows a dense core surrounded by filaments that bind gold-labeled secondary antibody to TMEM239 (black dots). [Courtesy of Ghetti et al., 2024.]

Then Ghetti collaborated with cryo-EM experts Goedert and Sjors Scheres, also at the MRC in Cambridge, to solve the structure of the fibril core to a resolution as 2.6Å.

The fibril cores, comprising amino acids 120 to 254 of the protein, folded much the same way as TMEM106B does in the most common of three different parenchymal fibrils (Apr 2022 news). The notable exception was between asparagines 164 and 183. A slight 4Å shift caused phenylalanine 237 to rotate, widening a cavity between the N terminal of this segment and the rest of the protein, and narrowing a cavity at the C terminal end (image below). Hydrophobic sides chains line the latter cavity, which contain rod-like molecules that run along the filament axis; they might be lipids. The cavity bordered by the N-terminal part of this segment is much smaller and may contain ions or water.

Familiar Fold. In Biondi bodies, the TMEM106b protofibril core (left) runs from serine 120 to glycine 254. It mimics the fold found previously except between asparagines 164 and 183 (right), where a 4Å shift between the Biondi (blue) and parenchymal (orange) fibrils results in the side chains of phenylalanines at position 237 to rotate in opposite directions [Courtesy of Ghetti et al., 2024.]

Why does TMEM106b form a slightly different fold? “It may be the result of the different cellular milieu in ependymal cells when compared to brain cells,” suggested the authors.

What might this discovery mean for neurodegenerative disease? Scientists contacted by Alzforum declined to speculate. Some called it a minor curiosity. That TMEM106b is made by many cells in the brain, and that its fibrils are found in various cell types and neurodegenerative diseases, may complicate any interpretation.—Tom Fagan

Comments

1. • Costantino Iadecola
     Weill College Medicine, New York
   • Posted: 02 Dec 2024

   The conclusion that the Biondi bodies may contribute to the reduction in CSF production in aging, and possibly in age related neurodegenerative disease in which CSF clearance may be reduced, is certainly of interest. Another aspect that could be of interest is a potential link between Biondi bodies and the tight junctions that connect adjacent ependymal cells. A disruption of the TJ could lead to entry into the CSF of deleterious blood products with possible pathogenic relevance.

   View all comments by Costantino Iadecola

Make a Comment

To make a comment you must login or register.

References

News Citations

1. Surprise! TMEM106b Fibrils Found in Neurodegenerative Diseases 12 Apr 2022

Paper Citations

1. del Rio Hortega P. Trab Lab Invest Biol Univ Madrid 15:367–378. 1918
2. Biondi G. Z ges Neurol Psychiat 144:161–165. 1933
3. Schweighauser M, Arseni D, Bacioglu M, Huang M, Lövestam S, Shi Y, Yang Y, Zhang W, Kotecha A, Garringer HJ, Vidal R, Hallinan GI, Newell KL, Tarutani A, Murayama S, Miyazaki M, Saito Y, Yoshida M, Hasegawa K, Lashley T, Revesz T, Kovacs GG, van Swieten J, Takao M, Hasegawa M, Ghetti B, Spillantini MG, Ryskeldi-Falcon B, Murzin AG, Goedert M, Scheres SH. Age-dependent formation of TMEM106B amyloid filaments in human brains. Nature. 2022 May;605(7909):310-314. Epub 2022 Mar 28 PubMed.

Further Reading

No Available Further Reading