1 Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, and Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA. 2 Howard Hughes Medical Institute, UCLA, Los Angeles, CA, 90095, USA. 3 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, 200030, China. 4 Mayo Clinic, Jacksonville, FL, 32224, USA. †These authors contributed equally to this work.

Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B, rather than TDP-43

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Yi Xiao Jiang1,2†, Qin Cao1,2,3†, Michael R. Sawaya1,2, Romany Abskharon1,2, Peng Ge1,2, Michael DeTure4, Dennis W. Dickson4, Janine Y. Fu1, Rachel R. Ogorzalek Loo1, Joseph A. Loo1, David S. Eisenberg1,2*. Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B, rather than TDP-43. Uploaded to https://www.posterpresentations.com/research/groups/UCLA/UCLA-6/. Submitted on April 21, 2022.

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Poster - #UCLA-6 - Keywords: neurodegeneration, amyloid, fibrils, cryo-EM, structural biology, TMEM106B, TDP-43, FTLD

Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B, rather than TDP-43

Yi Xiao Jiang1,2†, Qin Cao1,2,3†, Michael R. Sawaya1,2, Romany Abskharon1,2, Peng Ge1,2, Michael DeTure4, Dennis W. Dickson4, Janine Y. Fu1, Rachel R. Ogorzalek Loo1, Joseph A. Loo1, David S. Eisenberg1,2*
1 Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, and Molecular Biology Institute, UCLA, Los Angeles, CA, 90095, USA. 2 Howard Hughes Medical Institute, UCLA, Los Angeles, CA, 90095, USA. 3 Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, 200030, China. 4 Mayo Clinic, Jacksonville, FL, 32224, USA. †These authors contributed equally to this work.

ABSTRACT:
Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition, following only Alzheimer’s and Parkinson’s diseases. FTLD typically presents in 45-64-year-olds with behavioral changes or progressive decline of language skills. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions detected by TAR DNA-binding protein (TDP-43) immunoreactivity. Here, we extracted amyloid fibrils from brains of four patients, representing four out of five FTLD-TDP subclasses and determined their near-atomic resolution structures by cryogenic electron-microscopy (cryo-EM). Unexpectedly, all amyloid fibrils examined are composed of a 135-residue C-terminal fragment of transmembrane protein 106B (TMEM106B), a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP. In addition to TMEM106B fibrils, abundant non-fibrillar aggregated TDP-43 is present, as revealed by immunogold labeling. Our observations confirm that FTLD-TDP is an amyloid-involved disease and suggest that amyloid involvement in FTLD-TDP is of protein TMEM106B, rather than of TDP-43.