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Open Access Publications from the University of California

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

  • Author(s): Fanara, P
  • Wong, PYA
  • Husted, KH
  • Liu, S
  • Liu, VM
  • Kohlstaedt, LA
  • Riiff, T
  • Protasio, JC
  • Boban, D
  • Killion, S
  • Killian, M
  • Epling, L
  • Sinclair, E
  • Peterson, J
  • Price, RW
  • Cabin, DE
  • Nussbaum, RL
  • Brühmann, J
  • Brandt, R
  • Christine, CW
  • Aminoff, MJ
  • Hellerstein, MK
  • et al.

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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 synthesized2H-labeled neuronal proteins were transported to nerve terminals and secreted, and then appeared in CSF. In 3 mouse models of neurodegeneration, distinct2H-cargo proteins displayed delayed appearance and disappearance kinetics in the CSF, suggestive of aberrant transport kinetics. Microtubule-modulating pharmacotherapy normalized CSF-based kinetics of affected2H-cargo proteins and ameliorated neurodegenerative symptoms in mice. After2H2O 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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