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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
-
Amyloid beta-Protein Precursor / cerebrospinal fluid*
-
Amyloid beta-Protein Precursor / metabolism
-
Animals
-
Axonal Transport*
-
Biomarkers / cerebrospinal fluid
-
Case-Control Studies
-
Chromogranin B / cerebrospinal fluid*
-
Chromogranin B / metabolism
-
Female
-
Humans
-
Kinetics
-
Male
-
Mice
-
Mice, Transgenic
-
Microtubule-Associated Proteins / metabolism
-
Microtubules / metabolism
-
Mutation, Missense
-
Neuregulin-1 / cerebrospinal fluid*
-
Neuregulin-1 / metabolism
-
Nocodazole / pharmacology
-
Noscapine / pharmacology
-
Paclitaxel / pharmacology
-
Parkinson Disease, Secondary / cerebrospinal fluid*
-
Parkinson Disease, Secondary / chemically induced
-
Superoxide Dismutase / genetics
-
Superoxide Dismutase-1
-
Tubulin Modulators / pharmacology
-
alpha-Synuclein / cerebrospinal fluid*
-
alpha-Synuclein / metabolism
-
tau Proteins / metabolism
Substances
-
Amyloid beta-Protein Precursor
-
Biomarkers
-
Chromogranin B
-
Microtubule-Associated Proteins
-
Mtap2 protein, mouse
-
Neuregulin-1
-
Nrg1 protein, mouse
-
SOD1 protein, human
-
Snca protein, mouse
-
Tubulin Modulators
-
alpha-Synuclein
-
chromogranin B, mouse
-
tau Proteins
-
Noscapine
-
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
-
Sod1 protein, mouse
-
Superoxide Dismutase
-
Superoxide Dismutase-1
-
Paclitaxel
-
Nocodazole