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J Clin Invest. 2012 Sep;122(9):3159-69. doi: 10.1172/JCI64575. Epub 2012 Aug 27.

Cerebrospinal fluid-based kinetic biomarkers of axonal transport in monitoring neurodegeneration.

Author information

1
KineMed Inc., Emeryville, California 94608, USA. pfanara@kinemed.com

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.

PMID:
22922254
PMCID:
PMC3428100
DOI:
10.1172/JCI64575
[Indexed for MEDLINE]
Free PMC Article

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