Department of Neurology; RNA Therapeutics Institute; Department of Radiology; Li Weibo Institute for Rare Disease Research; Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences
Biological Factors | Nervous System Diseases | Neurology | Neuroscience and Neurobiology | Radiology
OBJECTIVE: The objective of this study is to develop a novel method for monitoring the integrity of motor neurons in vivo by quantifying net retrograde axonal transport.
METHODS: The method uses single photon emission computed tomography to quantify retrograde transport to spinal cord of tetanus toxin fragment C ((125) I-TTC) following intramuscular injection. We characterized the transport profiles in 3 transgenic mouse models carrying amyotrophic lateral sclerosis (ALS)-associated genes, aging mice, and SOD1(G93A) transgenic mice following CRISPR/Cas9 gene editing. Lastly, we studied the effect of prior immunization of tetanus toxoid on the transport profile of TTC.
RESULTS: This technique defines a quantitative profile of net retrograde axonal transport of TTC in living mice. The profile is distinctly abnormal in transgenic SOD1(G93A) mice as young as 65 days (presymptomatic) and worsens with disease progression. Moreover, this method detects a distinct therapeutic benefit of gene editing in transgenic SOD1(G93A) mice well before other clinical parameters (eg, grip strength) show improvement. Symptomatic transgenic PFN1(C71G/C71G) ALS mice display gross reductions in net retrograde axonal transport, which is also disturbed in asymptomatic mice harboring a human C9ORF72 transgene with an expanded GGGGCC repeat motif. In wild-type mice, net retrograde axonal transport declines with aging. Lastly, prior immunization with tetanus toxoid does not preclude use of this assay.
INTERPRETATION: This assay of net retrograde axonal transport has broad potential clinical applications and should be particularly valuable as a physiological biomarker that permits early detection of benefit from potential therapies for motor neuron diseases.
motor neurons, axonal transport, UMCCTS funding
Rights and Permissions
© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
DOI of Published Version
Lee PJ, Kennedy Z, Wang Y, Lu Y, Cefaliello C, Uyan Ö, Song CQ, da Cruz Godinho BM, Xu Z, Rusckowski M, Xue W, Brown RH Jr. Imaging Net Retrograde Axonal Transport In Vivo: A Physiological Biomarker. Ann Neurol. 2022 May;91(5):716-729. doi: 10.1002/ana.26329. Epub 2022 Mar 19. PMID: 35178738. Link to article on publisher's site
Annals of neurology
Lee P, Kennedy ZC, Wang Y, Lu Y, Cefaliello C, Uyan O, Song C, Godinho B, Xu Z, Rusckowski M, Xue W, Brown RH. (2022). Imaging Net Retrograde Axonal Transport In Vivo: A Physiological Biomarker. Radiology Publications. https://doi.org/10.1002/ana.26329. Retrieved from https://escholarship.umassmed.edu/radiology_pubs/677
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.