Tau filaments from amyotrophic lateral sclerosis/parkinsonism-dementia complex adopt the CTE fold

• DOI: 10.1073/pnas.2306767120
• Publication Date: 2023-12-15T18:31:56Z
• Authors: Chao Qi; Bert M. Verheijen; Yasumasa Kokubo; Yang Shi; Stephan Tetter; Alexey G. Murzin; Asa Nakahara; Satoru Morimoto; Marc Vermulst; Ryogen Sasaki; Eleonora Aronica; Yoshifumi Hirokawa; Kiyomitsu Oyanagi; Akiyoshi Kakita; Benjamin Ryskeldi...; Mari Yoshida; Masato Hasegawa; Sjors H. W. Scheres; Michel Goedert
• Keywords: tau Proteins; Neurodegenerative; 3101 Biochemistry and Cell Biology; Chronic Traumatic Encephalopathy; neurodegenerative disease; Rare Diseases; Parkinsonian Disorders; Japan; Acquired Cognitive Impairment; 2.1 Biological and endogenous factors; Humans; 2 Aetiology; chronic traumatic encephalopathy tau fold; amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS/PDC); Amyotrophic Lateral Sclerosis; Neurosciences; Neurodegenerative Diseases; Biological Sciences; Brain Disorders; Frontotemporal Dementia (FTD); Tauopathies; Neurological; tau filament assembly; Dementia; ALS; 31 Biological Sciences

The amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) of the island of Guam and the Kii peninsula of Japan is a fatal neurodegenerative disease of unknown cause that is characterized by the presence of abundant filamentous tau inclusions in brains and spinal cords. Here, we used electron cryo-microscopy to determine the structures of tau filaments from the cerebral cortex of three cases of ALS/PDC from Guam and eight cases from Kii, as well as from the spinal cord of two of the Guam cases. Tau filaments had the chronic traumatic encephalopathy (CTE) fold, with variable amounts of Type I and Type II filaments. Paired helical tau filaments were also found in three Kii cases and tau filaments with the corticobasal degeneration fold in one Kii case. We identified a new Type III CTE tau filament, where protofilaments pack against each other in an antiparallel fashion. ALS/PDC is the third known tauopathy with CTE-type filaments and abundant tau inclusions in cortical layers II/III, the others being CTE and subacute sclerosing panencephalitis. Because these tauopathies are believed to have environmental causes, our findings support the hypothesis that ALS/PDC is caused by exogenous factors.