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- Title
Cerebrospinal fluid-based kinetic biomarkers of axonal transport in monitoring neurodegeneration.
- Authors
Fanara, Patrizia; Wong, Po-Yin A; Husted, Kristofor H; Liu, Shanshan; Liu, Victoria M; Kohlstaedt, Lori A; Riiff, Timothy; Protasio, Joan C; Boban, Drina; Killion, Salena; Killian, Maudi; Epling, Lorrie; Sinclair, Elisabeth; Peterson, Julia; Price, Richard W; Cabin, Deborah E; Nussbaum, Robert L; Brühmann, Jörg; Brandt, Roland; Christine, Chadwick W; Aminoff, Michael J; Hellerstein, Marc K
- Abstract
Progress in neurodegenerative disease research is hampered by the lack of biomarkers of neuronal dysfunction. We here identified a class of cerebrospinal fluid-based (CSF-based) kinetic biomarkers that reflect altered neuronal transport of protein cargo, a common feature of neurodegeneration. After a pulse administration of heavy water (2H2O), distinct, newly synthesized 2H-labeled neuronal proteins were transported to nerve terminals and secreted, and then appeared in CSF. In 3 mouse models of neurodegeneration, distinct 2H-cargo proteins displayed delayed appearance and disappearance kinetics in the CSF, suggestive of aberrant transport kinetics. Microtubule-modulating pharmacotherapy normalized CSF-based kinetics of affected 2H-cargo proteins and ameliorated neurodegenerative symptoms in mice. After 2H2O labeling, similar neuronal transport deficits were observed in CSF of patients with Parkinson's disease (PD) compared with non-PD control subjects, which indicates that these biomarkers are translatable and relevant to human disease. Measurement of transport kinetics may provide a sensitive method to monitor progression of neurodegeneration and treatment effects.
- Publication
The Journal of clinical investigation, 2012, Vol 122, Issue 9, p3159
- ISSN
1558-8238
- Publication type
Journal Article
- DOI
10.1172/JCI64575