TY - JOUR
T1 - SILK studies — capturing the turnover of proteins linked to neurodegenerative diseases
AU - Paterson, Ross W.
AU - Gabelle, Audrey
AU - Lucey, Brendan P.
AU - Barthélemy, Nicolas R.
AU - Leckey, Claire A.
AU - Hirtz, Christophe
AU - Lehmann, Sylvain
AU - Sato, Chihiro
AU - Patterson, Bruce W.
AU - West, Tim
AU - Yarasheski, Kevin
AU - Rohrer, Jonathan D.
AU - Wildburger, Norelle C.
AU - Schott, Jonathan M.
AU - Karch, Celeste M.
AU - Wray, Selina
AU - Miller, Timothy M.
AU - Elbert, Donald L.
AU - Zetterberg, Henrik
AU - Fox, Nick C.
AU - Bateman, Randall J.
N1 - Funding Information:
R.W.P. is supported by a UK National Institute for Health Research (NIHR) academic clinical lectureship. H.Z. is a Wallenberg Academy Fellow and is supported by grants from the Swedish Research Council, the European Research Council, the Olav Thon Foundation and the UK Dementia Research Institute at University College London (UCL). A.G., C.H. and S.L.’s stable isotope labelling kinetics (SILK) work is supported by the French 2010 National Programme Hospitalier de Recherche Clinique (PHRC) ‘ProMara’, Direction de L’Hospitalisation et de l’Organisation des Soins (DHOS). S.W. is supported by an Alzheimer’s Research UK Senior Research Fellowship (ARUK-SRF2016B-2). B.P.L. is supported by a grant from the US National Institute on Aging (K76 AG054863). T.M.’s SILK studies are supported by US NIH grant R01-NS098716-01. C.M.K. is supported by NIH grant K01AG046374. N.C.F. acknowledges support from the NIHR UCL Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre and the UK Dementia Research Institute at UCL. R.J.B.’s SILK work was supported by the BrightFocus Foundation (grant A2014384S), Tau SILK Consortium (AbbVie, Biogen and Eli Lilly), NIH grant R01-NS095773, MetLife Foundation, Alzheimer’s Association Zenith Award Grant (institution grant #3856-80569), NIH (R01NS065667) and the Cure Alzheimer’s Fund.
Publisher Copyright:
© 2019, Springer Nature Limited.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - Alzheimer disease (AD) is one of several neurodegenerative diseases characterized by dysregulation, misfolding and accumulation of specific proteins in the CNS. The stable isotope labelling kinetics (SILK) technique is based on generating amino acids labelled with naturally occurring stable (that is, nonradioactive) isotopes of carbon and/or nitrogen. These labelled amino acids can then be incorporated into proteins, enabling rates of protein production and clearance to be determined in vivo and in vitro without the use of radioactive or chemical labels. Over the past decade, SILK studies have been used to determine the turnover of key pathogenic proteins amyloid-β (Aβ), tau and superoxide dismutase 1 (SOD1) in the cerebrospinal fluid of healthy individuals, patients with AD and those with other neurodegenerative diseases. These studies led to the identification of several factors that alter the production and/or clearance of these proteins, including age, sleep and disease-causing genetic mutations. SILK studies have also been used to measure Aβ turnover in blood and within brain tissue. SILK studies offer the potential to elucidate the mechanisms underlying various neurodegenerative disease mechanisms, including neuroinflammation and synaptic dysfunction, and to demonstrate target engagement of novel disease-modifying therapies.
AB - Alzheimer disease (AD) is one of several neurodegenerative diseases characterized by dysregulation, misfolding and accumulation of specific proteins in the CNS. The stable isotope labelling kinetics (SILK) technique is based on generating amino acids labelled with naturally occurring stable (that is, nonradioactive) isotopes of carbon and/or nitrogen. These labelled amino acids can then be incorporated into proteins, enabling rates of protein production and clearance to be determined in vivo and in vitro without the use of radioactive or chemical labels. Over the past decade, SILK studies have been used to determine the turnover of key pathogenic proteins amyloid-β (Aβ), tau and superoxide dismutase 1 (SOD1) in the cerebrospinal fluid of healthy individuals, patients with AD and those with other neurodegenerative diseases. These studies led to the identification of several factors that alter the production and/or clearance of these proteins, including age, sleep and disease-causing genetic mutations. SILK studies have also been used to measure Aβ turnover in blood and within brain tissue. SILK studies offer the potential to elucidate the mechanisms underlying various neurodegenerative disease mechanisms, including neuroinflammation and synaptic dysfunction, and to demonstrate target engagement of novel disease-modifying therapies.
UR - http://www.scopus.com/inward/record.url?scp=85068165997&partnerID=8YFLogxK
U2 - 10.1038/s41582-019-0222-0
DO - 10.1038/s41582-019-0222-0
M3 - Article
C2 - 31222062
AN - SCOPUS:85068165997
VL - 15
SP - 419
EP - 427
JO - Nature Reviews Neurology
JF - Nature Reviews Neurology
SN - 1759-4758
IS - 7
ER -