title: 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.affiliation: KineMed Inc., Emeryville, California 94608, USA. pfanara@kinemed.com
authors.forename: Patrizia
authors.initials: P
authors.lastname: Fanara
authors.forename: Po-Yin A
authors.initials: PY
authors.lastname: Wong
authors.forename: Kristofor H
authors.initials: KH
authors.lastname: Husted
authors.forename: Shanshan
authors.initials: S
authors.lastname: Liu
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Liu
authors.forename: Lori A
authors.initials: LA
authors.lastname: Kohlstaedt
authors.forename: Timothy
authors.initials: T
authors.lastname: Riiff
authors.forename: Joan C
authors.initials: JC
authors.lastname: Protasio
authors.forename: Drina
authors.initials: D
authors.lastname: Boban
authors.forename: Salena
authors.initials: S
authors.lastname: Killion
authors.forename: Maudi
authors.initials: M
authors.lastname: Killian
authors.forename: Lorrie
authors.initials: L
authors.lastname: Epling
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sinclair
authors.forename: Julia
authors.initials: J
authors.lastname: Peterson
authors.forename: Richard W
authors.initials: RW
authors.lastname: Price
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Cabin
authors.forename: Robert L
authors.initials: RL
authors.lastname: Nussbaum
authors.forename: Jörg
authors.initials: J
authors.lastname: Brühmann
authors.forename: Roland
authors.initials: R
authors.lastname: Brandt
authors.forename: Chadwick W
authors.initials: CW
authors.lastname: Christine
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Aminoff
authors.forename: Marc K
authors.initials: MK
authors.lastname: Hellerstein
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid* / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport; D015415:Biomarkers / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D053378:Chromogranin B / Q000134:cerebrospinal fluid* / Q000378:metabolism; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D020125:Mutation, Missense; D020890:Neuregulin-1 / Q000134:cerebrospinal fluid* / Q000378:metabolism; D015739:Nocodazole / Q000494:pharmacology; D009665:Noscapine / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000134:cerebrospinal fluid* / Q000139:chemically induced; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D050257:Tubulin Modulators / Q000494:pharmacology; D051844:alpha-Synuclein / Q000134:cerebrospinal fluid* / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D053378:Chromogranin B; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; C000606290:SOD1 protein, human; C497605:Snca protein, mouse; D050257:Tubulin Modulators; D051844:alpha-Synuclein; C506137:chromogranin B, mouse; D016875:tau Proteins; D009665:Noscapine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D017239:Paclitaxel; D015739:Nocodazole