Detection of TDP-43 oligomers in frontotemporal lobar degeneration-TDP.

Abstract

OBJECTIVE:

The proteinaceous inclusions in TDP-43 proteinopathies such as frontotemporal lobar degeneration (FTLD)-TDP are made of high-molecular-weight aggregates of TDP-43. These aggregates have not been classified as amyloids, as prior amyloid staining results were not conclusive. Here we used a specific TDP-43 amyloid oligomer antibody called TDP-O to determine the presence and abundance of TDP-43 oligomers among different subtypes of FTLD-TDP as well as in hippocampal sclerosis (HS), which represents a non-FTLD pathology with TDP-43 inclusions.

METHODS:

Postmortem tissue from the hippocampus and anterior orbital gyrus from 54 prospectively assessed and diagnosed subjects was used for immunostaining with TDP-O. Electron microscopy was used to assess the subcellular locations of TDP-O-decorated structures.

RESULTS:

TDP-43 inclusions staining with TDP-O were present in FTLD-TDP and were most conspicuous for FTLD-TDP type C, the subtype seen in most patients with semantic variant primary progressive aphasia. TDP-O immunoreactivity was absent in the hippocampus of HS patients despite abundant TDP-43 inclusions. Ultrastructurally, TDP-43 oligomers resided in granular or tubular structures, frequently in close proximity to, but not within, neuronal lysosomes.

INTERPRETATION:

TDP-43 forms amyloid oligomers in the human brain, which may cause neurotoxicity in a manner similar to other amyloid oligomers. Oligomer formation may contribute to the conformational heterogeneity of TDP-43 aggregates and mark the different properties of TDP-43 inclusions between FTLD-TDP and HS.

• Authors: Patricia F Kao, Yun-Ru Chen, Xiao-Bo Liu, Charles DeCarli, William W Seeley, Lee-Way Jin
• Journal: Annals of neurology (Ann Neurol) Vol. 78 Issue 2 Pg. 211-21 (Aug 2015) ISSN: 1531-8249 [Electronic] United States
• PMID: 25921485 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Neurological Association.

Chemical References

• Amyloid
• Biopolymers
• DNA-Binding Proteins
• TARDBP protein, human

Topics

• Aged
• Amyloid (metabolism)
• Amyotrophic Lateral Sclerosis (metabolism)
• Biopolymers (metabolism)
• DNA-Binding Proteins (metabolism, ultrastructure)
• Female
• Frontotemporal Lobar Degeneration (metabolism)
• Hippocampus (metabolism, pathology, ultrastructure)
• Humans
• Immunohistochemistry
• Male
• Microscopy, Electron
• Middle Aged
• Neurons (metabolism, ultrastructure)
• Prefrontal Cortex (metabolism, ultrastructure)
• Sclerosis