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

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

Yi Xiao Jiang ^1,2, Qin Cao ^1,2,3, Michael R Sawaya ^1,2, Romany Abskharon ^1,2, Peng Ge ^1,2, Michael DeTure ⁴, Dennis W Dickson ⁴, Janine Y Fu ¹, Rachel R Ogorzalek Loo ¹, Joseph A Loo ¹, David S Eisenberg ^5,6

Yi Xiao Jiang ^1,2, Qin Cao ^1,2,3, Michael R Sawaya ^1,2

¹Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, and Molecular Biology Institute, UCLA, Los Angeles, CA, USA.
²Howard Hughes Medical Institute, UCLA, Los Angeles, CA, USA.
³Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China.
⁴Mayo Clinic, Jacksonville, FL, USA.
⁵Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, and Molecular Biology Institute, UCLA, Los Angeles, CA, USA. david@mbi.ucla.edu.
⁶Howard Hughes Medical Institute, UCLA, Los Angeles, CA, USA. david@mbi.ucla.edu.

⁰Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute, and Molecular Biology Institute, UCLA, Los Angeles, CA, USA.

Nature +

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March 28, 2022

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View abstract on PubMed

Summary

This summary is machine-generated.

Frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) involves amyloid fibrils. These fibrils are unexpectedly formed by transmembrane protein 106B (TMEM106B), not TDP-43 itself.

Area Of Science

Neurodegenerative diseases
Molecular biology
Protein biochemistry

Background

Frontotemporal lobar degeneration (FTLD) is a common neurodegenerative disorder.
FTLD-TDP is a subtype characterized by TAR DNA-binding protein (TDP-43) inclusions.
TMEM106B is a known genetic risk factor for FTLD-TDP.

Purpose Of The Study

To determine the composition of amyloid fibrils in FTLD-TDP.
To investigate the structural basis of FTLD-TDP pathology.

Main Methods

Cryo-electron microscopy to determine fibril structures.
Amyloid fibril extraction from patient brain samples.
Immunogold labeling to detect aggregated proteins.

Main Results

Amyloid fibrils were extracted from four FTLD-TDP patient brains.
All examined fibrils were composed of TMEM106B, not TDP-43.
Abundant non-fibrillar aggregated TDP-43 was also detected.

Conclusions

FTLD-TDP pathology involves amyloid fibrils.
These fibrils are formed by TMEM106B, challenging previous assumptions.
TMEM106B aggregation is central to FTLD-TDP pathogenesis.

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Amyloid Fibrils

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Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...

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