Cerebrospinal fluid-based kinetic biomarkers of axonal transport in monitoring neurodegeneration
Autor(en): | Fanara, Patrizia Wong, Po-Yin A. Husted, Kristofor H. Liu, Shanshan Liu, Victoria M. Kohlstaedt, Lori A. Riiff, Timothy Protasio, Joan C. Boban, Drina Killion, Salena Killian, Maudi Epling, Lorrie Sinclair, Elisabeth Peterson, Julia Price, Richard W. Cabin, Deborah E. Nussbaum, Robert L. Bruehmann, Joerg Brandt, Roland Christine, Chadwick W. Aminoff, Michael J. Hellerstein, Marc K. |
Stichwörter: | ALPHA-SYNUCLEIN; HEAVY-WATER; HYPERDYNAMIC MICROTUBULES; LOCALIZATION; Medicine, Research & Experimental; MOUSE MODEL; NEURONS; NEUROTROPHINS; PARKINSONS-DISEASE; PROTEIN; Research & Experimental Medicine; TRAFFICKING | Erscheinungsdatum: | 2012 | Herausgeber: | AMER SOC CLINICAL INVESTIGATION INC | Journal: | JOURNAL OF CLINICAL INVESTIGATION | Volumen: | 122 | Ausgabe: | 9 | Startseite: | 3159 | Seitenende: | 3169 | Zusammenfassung: | 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 ((H2O)-H-2), distinct, newly synthesized H-2-labelecl neuronal proteins were transported to nerve terminals and secreted, and then appeared in CSF. In 3 mouse models of neurodegeneration, distinct H-2-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 (H2O)-H-2 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. |
ISSN: | 00219738 | DOI: | 10.1172/JCI64575 |
Zur Langanzeige
Seitenaufrufe
1
Letzte Woche
0
0
Letzter Monat
0
0
geprüft am 19.05.2024