@article{2c8ab77962e74b05b6d4c772114909dd,
title = "Guam ALS-PDC is a distinct double-prion disorder featuring both tau and Aβ prions",
abstract = "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.",
keywords = "Aβ, Guam, Prions, neurodegeneration, tau",
author = "Carlo Condello and Ayers, {Jacob I.} and Dalgard, {Clifton L.} and Garcia, {M. Madhy Garcia} and Rivera, {Brianna M.} and Seeley, {William W.} and Perl, {Daniel P.} and Prusiner, {Stanley B.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Charles Rice, Jonathan Woodson, Walter Tinling, and Kevin Kelly for their support and encouragement in many different phases of this study.This work was supported by grants from the NIH (AG002132 and AG031220), as well as by the Dana Foundation, the Glenn Foundation, the Henry M. Jackson Foundation, the Rainwater Charitable Foundation, and the Sherman Fairchild Foundation. We thank Amanda L. Woerman (UCSF) for her contribution to the initial study.We thank Ann A.Lazar (Biostatistics,UCSF) for her assistance with statistical analyses. We thank Joaquin Villar (Center for Military Funding Information: We thank Charles Rice, Jonathan Woodson, Walter Tinling, and Kevin Kelly for their support and encouragement in many different phases of this study. This work was supported by grants from the NIH (AG002132 and AG031220), as well as by the Dana Foundation, the Glenn Foundation, the Henry M. Jackson Foundation, the Rainwater Charitable Foundation, and the Sherman Fairchild Foundation. We thank Amanda L. Woerman (UCSF) for her contribution to the initial study. We thank Ann A. Lazar (Biostatistics, UCSF) for her assistance with statistical analyses. We thank Joaquin Villar (Center for Military Precision Health, Uniformed Services University of the Health Sciences) for his assistance with genome sequencing analysis and gene variant interpretation. We thank Douglas Galasko (University of California San Diego) for providing the clinical reports associated with the Guamanian ALS-PDC and control samples. Human brain tissue was received from the UCSF Neurodegenerative Disease Brain Bank, which is supported by the NIH (AG023501 and AG19724 to W.W.S.), the Tau Consortium, and the Consortium for Frontotemporal Dementia Research. The work was also supported by the NIH (P01AG14382), the Department of Defense/ Uniformed Services University Brain Tissue Repository and Neuropathology Core [Defense Health Agency (DHA) Grant #HU0001-17-2-0029], and the UCSF/ Uniformed Services University of the Health Sciences Partnership to Develop Tau Prion Therapeutics for Chronic Traumatic Encephalopathy - Brain Injury and Disease Prevention, Treatment & Research (DHA Grant #HU0001-19-2-000). The opinions expressed here are those of the authors and are not necessarily representative of those of the Uniformed Services University, the United States Department of Defense or the United States Army, Navy, Air Force, or any other Federal agency. Funding Information: Precision Health, Uniformed Services University of the Health Sciences) for his assistance with genome sequencing analysis and gene variant interpretation. We thank Douglas Galasko (University of California San Diego) for providing the clinical reports associated with the Guamanian ALS-PDC and control samples. Human brain tissue was received from the UCSF Neurodegenerative Disease Brain Bank, which is supported by the NIH (AG023501 and AG19724 to W.W.S.), the Tau Consortium,and the Consortium for Frontotemporal Dementia Research.The work was also supported by the NIH (P01AG14382), the Department of Defense/ Uniformed Services University Brain Tissue Repository and Neuropathology Core [Defense Health Agency (DHA) Grant #HU0001-17-2-0029], and the UCSF/ Uniformed Services University of the Health Sciences Partnership to Develop Tau Prion Therapeutics for Chronic Traumatic Encephalopathy—Brain Injury and Disease Prevention, Treatment & Research (DHA Grant #HU0001-19-2-000). The opinions expressed here are those of the authors and are not necessarily representative of those of the Uniformed Services University, the United States Department of Defense or the United States Army, Navy, Air Force, or any other Federal agency. Funding Information: vided written or verbal consent to donate autopsied brains for use in biomedical research in accordance with the standards of each institution. Fresh-frozen autopsied brain tissue was procured from the brain biorepositories at UCSF and the Guam Brain Specimen repository of the Micronesian Health Study, directed by Dr. Daniel Perl and funded by the National Institute on Aging for over 20 y. It is currently housed at the Uniformed Services University of the Health Sciences in Bethesda, MD. SI Appendix, Tables S1 and S2 include available demographic and clinicopathological information of patient donors. Frozen brain tissues were thawed and weighed to determine the mass in grams. Tissue was mechanically homogenized in nine volumes of cold Dulbecco's phosphate-buffered saline (DPBS) containing Halt Protease Inhibitor Cocktail (1×,Thermo Fisher Scientific), using a handheld probe-tip homogenizer (OMNI International).The homogenate was clarified by centrifugation at 5,000 × g for 5 min at 4 °C, and supernatants were collected and stored at −80 °C. Publisher Copyright: {\textcopyright} 2023 the Author(s).",
year = "2023",
month = mar,
day = "28",
doi = "10.1073/pnas.2220984120",
language = "English",
volume = "120",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "13",
}