Imaging Net Retrograde Axonal Transport In Vivo: A Physiological Biomarker
AuthorsLee, Pin-Tsun Justin
Kennedy, Zachary C.
Godinho, Bruno M D C
Brown, Robert H. Jr.
UMass Chan AffiliationsGraduate School of Biomedical Sciences
Department of Biochemistry and Molecular Pharmacology
Li Weibo Institute for Rare Disease Research
Department of Radiology
RNA Therapeutics Institute
Department of Neurology
Document TypeJournal Article
Nervous System Diseases
Neuroscience and Neurobiology
MetadataShow full item record
AbstractOBJECTIVE: 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.
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