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

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.

Chronic lithium administration in a mouse model for Krabbe disease

“…These results are in accordance with the motor experiments ones, which showed no major changes in the performance of lithium‐treated mice. All the just above‐mentioned markers resulted significantly higher in TWI mice in respect of the healthy WT controls, confirming previous results 29,39 …”

“…All the just above‐mentioned markers resulted significantly higher in TWI mice in respect of the healthy WT controls, confirming previous results. 29 , 39 …”

“…All the just abovementioned markers resulted significantly higher in TWI mice in respect of the healthy WT controls, confirming previous results. 29,39 In order to further characterise the KD-related parameters in the brain of TWI-Li mice, we also measured the GALC enzymatic activity. As already found, GALC enzymatic activity was approximately zero in the brain of the untreated TWI mice, in accordance with the fact that this mouse model contains a premature stop codon in the GALC gene that abolishes enzymatic activity.…”

“…535/2018‐PR; official starting date: 9 July 2018). As previously done by our group, 20 , 27 , 39 mice genomic DNA was extracted from clipped tails PND 10–15 mice (EUROGOLD Tissue‐DNA Mini Kit, EUROCLONE) and the genetic status of each mouse was determined from the genome analysis of the TWI mutation, as reported from Sakai and co‐workers. 40 TWI, wild type (WT), and HET animals were all used for the experiments, and the HET littermates were also retained for colony maintenance.…”

Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches

“…The authors provided an extensive list of axon guidance diseases exhibiting clinical features resembling those of lysosomal disorders [17]. Tonazzini and colleagues described through the Twicher (TWI) mouse, the most used model of Krabbe disease, the onset of visual impairment, reduced contrast sensitivity, and neuropathological signs, including astrogliosis and reduced myelination in the early life stages [18]. Finally, De Pasquale and collaborators reported the application of a label-free quantitative proteomic approach in a mucopolysaccharidosis type IIIb mouse model, which enabled the classification of three major clusters of proteins dysregulated in the diseased brain [19].…”