Cleaved TMEM106B forms amyloid aggregates in central and peripheral nervous systems

Mehtap Bacioglu, Manuel Schweighauser, Derrick Gray, Sofia Lövestam, Taxiarchis Katsinelos, Annelies Quaegebeur, John van Swieten, Zane Jaunmuktane, Stephen W. Davies, Sjors H.W. Scheres, Michel Goedert, Bernardino Ghetti, Maria Grazia Spillantini*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Filaments made of residues 120-254 of transmembrane protein 106B (TMEM106B) form in an age-dependent manner and can be extracted from the brains of neurologically normal individuals and those of subjects with a variety of neurodegenerative diseases. TMEM106B filament formation requires cleavage at residue 120 of the 274 amino acid protein; at present, it is not known if residues 255-274 form the fuzzy coat of TMEM106B filaments. Here we show that a second cleavage appears likely, based on staining with an antibody raised against residues 263-274 of TMEM106B. We also show that besides the brain TMEM106B inclusions form in dorsal root ganglia and spinal cord, where they were mostly found in non-neuronal cells. We confirm that in the brain, inclusions were most abundant in astrocytes. No inclusions were detected in heart, liver, spleen or hilar lymph nodes. Based on their staining with luminescent conjugated oligothiophenes, we confirm that TMEM106B inclusions are amyloids. By in situ immunoelectron microscopy, TMEM106B assemblies were often found in structures resembling endosomes and lysosomes.

Original languageEnglish
Article number99
JournalActa neuropathologica communications
Volume12
Issue number1
DOIs
Publication statusE-pub ahead of print - 17 Jun 2024

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Publisher Copyright: © The Author(s) 2024.

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