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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Technical Advance

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 3

Differential delays in transport rates of neuronal cargo proteins in symptomatic SOD1G93A mice and MPTP-infused mice.

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Differential delays in transport rates of neuronal cargo proteins in sym...
(A) Delays in the time of appearance, Tmax, and disappearance of 2H-CHGB, 2H-NRG1, and 2H-sAPPα were observed in CSF from symptomatic 13-week-old SOD1G93A mice compared with age-matched WT controls (n = 5 male and 5 female per time point in duplicate, mean ± SD). The appearance curve of 2H-sAPPα suggested less of an effect in delay of secretion rates than that measured for 2H-NRG1 and 2H-CHGB in CSF from symptomatic 13-week-old SOD1G93A animals. CSF secretion kinetics of 2H-SNCA did not change compared with age-matched WT mice. CSF was collected 1, 2, 3, 5, and 10 days after labeling. 2H-labeled cargo proteins were sequentially immunoprecipitated and purified to homogeneity from albumin/Ig-depleted CSF. *P < 0.001. (B) Delays in the time of appearance, Tmax, and disappearance of 2H-CHGB, 2H-SNCA and 2H-sAPPα were observed in CSF from symptomatic MPTP-injected 8-week-old male mice compared with age-matched vehicle controls (n = 10 per time point in duplicate, mean ± SD). CSF secretion kinetics of 2H-NRG1 did not change compared with age-matched vehicle control mice. Mice received a pulse 2H2O labeling at 10 days after the last MPTP injection, and CSF was collected from vehicle- and MPTP-injected mice 1, 2, 3, 5, and 10 days after labeling. 2H-labeled cargo proteins were sequentially immunoprecipitated and purified to homogeneity from albumin/Ig-depleted CSF. *P < 0.001.