Prion-like properties of aggregated TDP-43 in diseased brains

Takashi Nonaka, Masato Hasegawa

Department of Neuropathology and Cell Biology, Dementia Research Project, Tokyo Metropolitan Institute of Medical Science

TDP-43 is the major component protein of ubiquitin-positive inclusions in brains of patients with frontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). We report the characterization of prion-like properties of aggregated TDP-43 prepared from diseased brains. When insoluble TDP-43 from brains was introduced as seeds into cultured cells expressing TDP-43, phosphorylated and ubiquitinated TDP-43 was aggregated in a self-templating manner. We found that the C-terminal fragments of insoluble TDP-43 characteristic of each disease type acted as seeds, inducing seed-dependent aggregation of TDP-43 in these cells. The seeding ability of insoluble TDP-43 was unaffected by proteinase treatment, but was abrogated by formic acid. Insoluble fraction from cells harboring TDP-43 aggregates could also trigger intracellular TDP-43 aggregation. These results indicate that insoluble TDP-43 has prion-like properties that may play a role in progression of TDP-43 proteinopathy.

Address correspondence to Dr. Takashi Nonaka, Department of Neuropathology and Cell Biology, Dementia Research Project, Tokyo Metropolitan Institute of Medical Science (2-1-6, Kamikitazawa, Setagaya-ku, 156-8506 Tokyo, Japan)