1. Cerebrospinal fluid-based kinetic biomarkers of axonal transport in monitoring neurodegeneration.
- Author
-
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, and Hellerstein, Marc K
- Subjects
Microtubules ,Animals ,Mice ,Transgenic ,Humans ,Mice ,Parkinson Disease ,Secondary ,Paclitaxel ,Noscapine ,1-Methyl-4-phenyl-1 ,2 ,3 ,6-tetrahydropyridine ,Nocodazole ,Superoxide Dismutase ,Neuregulin-1 ,Amyloid beta-Protein Precursor ,Microtubule-Associated Proteins ,tau Proteins ,Case-Control Studies ,Axonal Transport ,Kinetics ,Mutation ,Missense ,Female ,Male ,Tubulin Modulators ,alpha-Synuclein ,Chromogranin B ,Biomarkers ,Superoxide Dismutase-1 ,Neurosciences ,Dementia ,Brain Disorders ,Aging ,Neurodegenerative ,Acquired Cognitive Impairment ,Parkinson's Disease ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Medical and Health Sciences ,Immunology - 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.
- Published
- 2012