Visual System Impairment in a Mouse Model of Krabbe Disease: The Twitcher Mouse.

Ilaria Tonazzini,Marco Cecchini,Matteo Caleo,Ambra Del Grosso,Manuela Allegra,Chiara Cerri,Sara Antonini

doi:10.3390/biom11010007

Abstract

Krabbe disease (KD, or globoid cell leukodystrophy; OMIM #245200) is an inherited neurodegenerative condition belonging to the class of the lysosomal storage disorders. It is caused by genetic alterations in the gene encoding for the enzyme galactosylceramidase, which is responsible for cleaving the glycosydic linkage of galatosylsphingosine (psychosine or PSY), a highly cytotoxic molecule. Here, we describe morphological and functional alterations in the visual system of the Twitcher (TWI) mouse, the most used animal model of Krabbe disease. We report in vivo electrophysiological recordings showing defective basic functional properties of the TWI primary visual cortex. In particular, we demonstrate a reduced visual acuity and contrast sensitivity, and a delayed visual response. Specific neuropathological alterations are present in the TWI visual cortex, with reduced myelination, increased astrogliosis and microglia activation, and around the whole brain. Finally, we quantify PSY content in the brain and optic nerves by high-pressure liquid chromatography-mass spectrometry methods. An increasing PSY accumulation with time, the characteristic hallmark of KD, is found in both districts. These results represent the first complete characterization of the TWI visual system. Our data set a baseline for an easy testing of potential therapies for this district, which is also dramatically affected in KD patients.

Highlights

Krabbe disease (KD, or globoid cell leukodystrophy; OMIM #245200) is an inherited neurodegenerative condition belonging to the class of the lysosomal storage disorders (LSDs)
In order to assess the functional impairments of the TWI mouse visual system, we performed visual evoked potential (VEP) recordings and measured the basic physiological parameters of the primary visual cortex
VEPs from the binocular visual cortex were recorded in vivo in PND30-P36 mice, blind to genotype at a depth of 100 or 400 μm into the cortex in response to patterned stimuli

Summary

Introduction

Krabbe disease (KD, or globoid cell leukodystrophy; OMIM #245200) is an inherited neurodegenerative condition belonging to the class of the lysosomal storage disorders (LSDs). It is caused by multiple genetic alterations in the gene encoding for the enzyme galactosylceramidase (GALC; EC 3.2.1.46) or, in some rare cases, for the Sphingolipid activator protein saposin A (SapA) [1]. The GALC-SapA complex is responsible for cleaving the glycosydic linkage of galatosylsphingosine (psychosine or PSY), a highly cytotoxic molecule which is able to insert into the cell membrane, disrupt raft architecture, and presumably deregulate multiple cell signaling cascades [3,4]. The most proved explanations about KD molecular pathogenesis sustain that PSY primarily causes a massive death of oligodendrocytes and Schwann cells with consequent demyelination

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Conclusion