title: High-throughput screening of stem cell therapy for globoid cell leukodystrophy using automated neurophenotyping of twitcher mice.
abstract: Globoid cell leukodystrophy (Krabbe's disease) is an autosomal recessive neurodegenerative disorder that results from the deficiency of galactosylceramidase, a lysosomal enzyme involved in active myelination. Due to the progressive, lethal nature of this disease and the limited treatment options available, multiple laboratories are currently exploring novel therapies using the mouse model of globoid cell leukodystrophy. In order to establish a protocol for motor function assessment of the twitcher mouse, this study tested the capability of an automated system to detect phenotypic differences across mouse genotypes and/or treatment groups. The sensitivity of this system as a screening tool for the assessment of therapeutic interventions was determined by the administration of murine bone marrow-derived stem cells into twitcher mice via intraperitoneal injection. Animal behavior was analyzed using the Noldus EthoVision XT7 software. Novel biomarkers, including abnormal locomotion (e.g., velocity, moving duration, distance traveled, turn angle) and observed behaviors (e.g., rearing activity, number of defecation boli), were established for the twitcher mouse. These parameters were monitored across all mouse groups, and the automated system detected improved locomotion in the treated twitcher mice based on the correction of angular velocity, turn angle, moving duration, and exploratory behavior, such as thigmotaxis. Further supporting these findings, the treated mice showed improved lifespan, gait, wire hang ability, twitching severity and frequency, and sciatic nerve histopathology. Taken together, these data demonstrate the utility of computer-based neurophenotyping for motor function assessment of twitcher mice and support its utility for detecting the efficacy of stem cell-based therapy for neurodegenerative disorders.
authors.affiliation: Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-99, New Orleans, LA 70112, USA; Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, LA 70112, USA.
authors.forename: Brittni A
authors.initials: BA
authors.lastname: Scruggs
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, 2000 Percival Stern Hall, 6400 Freret Street, New Orleans, LA 70118, USA.
authors.forename: Annie C
authors.initials: AC
authors.lastname: Bowles
authors.affiliation: Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-99, New Orleans, LA 70112, USA.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-99, New Orleans, LA 70112, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Semon
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, LA 70112, USA.
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Kyzar
authors.affiliation: Department of Biostatistics & Bioinformatics, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, Suite 2001, New Orleans, LA 70112, USA.
authors.forename: Leann
authors.initials: L
authors.lastname: Myers
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, LA 70112, USA.
authors.forename: Allan V
authors.initials: AV
authors.lastname: Kalueff
authors.affiliation: Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-99, New Orleans, LA 70112, USA; Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, SL-83, New Orleans, LA 70112, USA. Electronic address: bbunnell@tulane.edu.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Bunnell
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006120:Grooming; D057166:High-Throughput Screening Assays; D007274:Injections, Intraperitoneal; D007965:Leukodystrophy, Globoid Cell / Q000473:pathology / Q000523:psychology* / Q000628:therapy*; D008017:Life Expectancy; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D010641:Phenotype; D011597:Psychomotor Performance / Q000502:physiology; D033581:Stem Cell Transplantation / Q000379:methods*
chemical_list: D049452:Green Fluorescent Proteins