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Unexpected Protein TMEM106B Could Play Role in Frontotemporal Lobar Degeneration
Biochemists at UCLA found that a little-known protein called TMEM106B composes the amyloid fibrils present in the brains of patients with frontotemporal lobar degeneration (FTLD), according to findings published in Nature. FTLD is the most common neurodegenerative disorder after Alzheimer and Parkinson Diseases, and these results will likely bring a new focus to the role that TMEM106B plays in related neurological diseases.
"[A]t the least, the present paper will alert the community of researchers studying neurodegeneration that a new protein may potentially play a role," said David Eisenberg, PhD, Distinguished Professor and P.D. Boyer Chair in the Department of Biochemistry at UCLA, of the research conducted in his lab by graduate student Yi Xiao Jiang and postdoctoral fellow Qin Cao.
The researchers extracted amyloid fibrils from frozen brain tissue provided by the Mayo Clinic originating from 4 deceased patients who had been diagnosed with FTLD-TDP. Through cryogenic electron microscopy (cryo-EM) they determined that the fibrils were constituted entirely by TMEM106B.
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Scientists have been aware for some time that amyloid fibrils likely influence the development and progression of neurodegenerative disorders. Further, previous studies have shown that the form of FTLD under examination in this study is typically characterized by the presence of molecular structures within brain cells composed of the protein TDP-43. Consequently, the UCLA research team was surprised to find that the amyloid fibrils of their subjects with FTLD were made up solely of TMEM106B.
Though linked to over 50 neurodegenerative diseases, little is known about TMEM106B. The study results also revealed that the structure of the protein shares commonalities with the fibrils observed in Alzheimer and Parkinson Diseases, but are more complex. Eisenberg describes its structure as a “golf course-like fold” due to the way that the thousands of layers of protein molecules, each with straight segments and bent corners, fold into its intricate shape.
"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.”
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