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.

Department(s)

Biological Sciences

Comments

The research was supported by grant number R21-NS059665 National Institutes of Neurological Disorders and Stroke, National Institutes of Health and Tulane University .

Keywords and Phrases

Behavioral phenotype; EthoVision XT7; Globoid cell leukodystrophy; Mesenchymal stem/stromal cells; Noldus technology; Twitcher mouse

International Standard Serial Number (ISSN)

0166-4328

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2013 Elsevier B.V., All rights reserved.

PubMed ID

22951180

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