Guam ALS-PDC is a distinct double-prion disorder featuring both tau and Aβ prions

The amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) of Guam is an endemic neurodegenerative disease that features widespread tau tangles, occasional α-synuclein Lewy bodies, and sparse β-amyloid (Aβ) plaques distributed in the central nervous system. Extensive studies of geneti...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2023-03, Vol.120 (13), p.e2220984120-e2220984120
Main Authors: Condello, Carlo, Ayers, Jacob I, Dalgard, Clifton L, Garcia Garcia, M Madhy, Rivera, Brianna M, Seeley, William W, Perl, Daniel P, Prusiner, Stanley B
Format: Article
Language:English
Subjects:
alpha-Synuclein
Alzheimer Disease
Alzheimer's disease
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - metabolism
Basal ganglia
Bioassays
Biological Sciences
Brain
Central nervous system
Central nervous system diseases
Dementia - metabolism
Dementia disorders
Down's syndrome
Environmental factors
Humans
Impairment
Infectivity
Least squares method
Lewy bodies
Movement disorders
Neurodegenerative Diseases
Neurological complications
Parkinsonian Disorders - metabolism
Prion Diseases
Prion protein
Prions
Senile plaques
Synuclein
Tau protein
tau Proteins - metabolism
β-Amyloid
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Summary:The amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) of Guam is an endemic neurodegenerative disease that features widespread tau tangles, occasional α-synuclein Lewy bodies, and sparse β-amyloid (Aβ) plaques distributed in the central nervous system. Extensive studies of genetic or environmental factors have failed to identify a cause of ALS-PDC. Building on prior work describing the detection of tau and Aβ prions in Alzheimer's disease (AD) and Down syndrome brains, we investigated ALS-PDC brain samples for the presence of prions. We obtained postmortem frozen brain tissue from 26 donors from Guam with ALS-PDC or no neurological impairment and 71 non-Guamanian donors with AD or no neurological impairment. We employed cellular bioassays to detect the prion conformers of tau, α-synuclein, and Aβ proteins in brain extracts. In ALS-PDC brain samples, we detected high titers of tau and Aβ prions, but we did not detect α-synuclein prions in either cohort. The specific activity of tau and Aβ prions was increased in Guam ALS-PDC compared with sporadic AD. Applying partial least squares regression to all biochemical and prion infectivity measurements, we demonstrated that the ALS-PDC cohort has a unique molecular signature distinguishable from AD. Our findings argue that Guam ALS-PDC is a distinct double-prion disorder featuring both tau and Aβ prions.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2220984120