Cerebrospinal fluid–based kinetic biomarkers of axonal transport in monitoring neurodegeneration
Patrizia Fanara, … , Michael J. Aminoff, Marc K. Hellerstein
Patrizia Fanara, … , Michael J. Aminoff, Marc K. Hellerstein
Published August 27, 2012
Citation Information: J Clin Invest. 2012;122(9):3159-3169. https://doi.org/10.1172/JCI64575.
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Cerebrospinal fluid–based kinetic biomarkers of axonal transport in monitoring neurodegeneration

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.

Authors

Patrizia Fanara, Po-Yin A. Wong, Kristofor H. Husted, Shanshan Liu, Victoria M. Liu, Lori A. Kohlstaedt, Timothy Riiff, Joan C. Protasio, Drina Boban, Salena Killion, Maudi Killian, Lorrie Epling, Elisabeth Sinclair, Julia Peterson, Richard W. Price, Deborah E. Cabin, Robert L. Nussbaum, Jörg Brühmann, Roland Brandt, Chadwick W. Christine, Michael J. Aminoff, Marc K. Hellerstein

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Figure 7

Model and kinetic interpretation of transport dynamics of released cargo proteins in CSF.

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Model and kinetic interpretation of transport dynamics of released cargo...
Newly synthesized cargo proteins destined for secretion travel from the cell body of neurons, where they are primarily produced, to the nerve terminal, where they are released into the CSF. MT-based transport kinetics are based on the timing of appearance and disappearance of newly synthesized 2H-labeled neuronal cargo proteins in CSF, after in vivo metabolic labeling. The differences between kinetics of appearance in and disappearance from CSF of 2H-CHGB and 2H-NRG1 in controls and PD subjects are summarized. Solid and dashed lines represent the curve fits of the data for controls and PD volunteers, respectively. CHGB and NRG1 concentrations were both markedly reduced in CSF of PD subjects (see Table 2). Delayed kinetics of appearance in and disappearance from CSF of 2H-labeled cargo proteins were independent of CSF protein concentrations.