Cerebrospinal Fluid-based Kinetic Biomarkers of Axonal Transport in Monitoring Neurodegeneration

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2012 Aug 28

PMID 22922254

Citations 27

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

Jorg Bruhmann

Roland Brandt

Chadwick W Christine

Michael J Aminoff

Marc K Hellerstein

Affiliations

Soon will be listed here.

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.

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