Comprehensive behavioral and biochemical outcomes of novel murine models of GM1-gangliosidosis and Morquio syndrome type B

Przybilla, Michael; Ou, Li; Tăbăran, Alexandra; Jiang, Xuntian; Sidhu, Rohini; Kell, Pamela; Ory, Daniel S.; O’Sullivan, M. Gerard; Whitley, Chester B.

doi:10.1016/j.ymgme.2018.11.002

Cited by 26 publications

(27 citation statements)

References 49 publications

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“…Marked cytoplasmic neuronal vacuolization was already present in clinically unremarkable two-month-old animals, suggesting that either a low amount of storage material does not cause functional damage or potential compensatory mechanisms can prevent neurologic dysfunctions in the first months of age. Clinical signs, including movement disorders, loss of righting reflex and emaciation developed at approximately four months of age, similar to previously described mouse models [22][23][24]68,70]. Ultrastructurally, neuronal vacuoles were found to be composed of concentric and partly lamellated material as described before in mice [22,23], American black bears [21], Alaskan Huskies [48], and humans [47].…”

Section: Discussionsupporting

confidence: 83%

“…Different mouse models for G M1 -gangliosidosis have been generated and investigated previously [22][23][24]. Hahn et al (1997) created Glb1 knockout mice by inserting a neomycin resistance gene into the middle of exon 6 [22].…”

Section: Introductionmentioning

confidence: 99%

“…Another Glb1 knockout mouse model was created by Matsuda et al (1997) by inserting a neomycin resistance cassette into exon 15 [23]. Przybilla et al (2019) targeted exon 8 of the murine Glb1 to generate a knockout mouse model [24]. All mouse models developed lesions characteristic of G M1 -gangliosidosis [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

“…Przybilla et al (2019) targeted exon 8 of the murine Glb1 to generate a knockout mouse model [24]. All mouse models developed lesions characteristic of G M1 -gangliosidosis [22][23][24]. Furthermore, feline models have been utilized in therapy trials, particularly gene therapy [49,50].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, feline models have been utilized in therapy trials, particularly gene therapy [49,50]. The mouse models were classified as [23] or compared with [22,24] the infantile or juvenile form of G M1 -gangliosidosis despite the late onset of the disease. Moreover, myelin changes have not been described so far.…”

Section: Introductionmentioning

confidence: 99%

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Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Eikelberg¹,

Lehmbecker²,

Brogden³

et al. 2020

JCM

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GM1-gangliosidosis is caused by a reduced activity of β-galactosidase (Glb1), resulting in intralysosomal accumulations of GM1. The aim of this study was to reveal the pathogenic mechanisms of GM1-gangliosidosis in a new Glb1 knockout mouse model. Glb1−/− mice were analyzed clinically, histologically, immunohistochemically, electrophysiologically and biochemically. Morphological lesions in the central nervous system were already observed in two-month-old mice, whereas functional deficits, including ataxia and tremor, did not start before 3.5-months of age. This was most likely due to a reduced membrane resistance as a compensatory mechanism. Swollen neurons exhibited intralysosomal storage of lipids extending into axons and amyloid precursor protein positive spheroids. Additionally, axons showed a higher kinesin and lower dynein immunoreactivity compared to wildtype controls. Glb1−/− mice also demonstrated loss of phosphorylated neurofilament positive axons and a mild increase in non-phosphorylated neurofilament positive axons. Moreover, marked astrogliosis and microgliosis were found, but no demyelination. In addition to the main storage material GM1, GA1, sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current Glb1−/− mice exhibit a so far undescribed axonopathy and a reduced membrane resistance to compensate the functional effects of structural changes. They can be used for detailed examinations of axon–glial interactions and therapy trials of lysosomal storage diseases.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Eikelberg¹,

Lehmbecker²,

Brogden³

et al. 2020

JCM

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Gene therapy approaches for GM1 gangliosidosis: Focus on animal and cellular studies

Hosseini,

Fallahi,

Tabei

et al. 2023

Cell Biochemistry & Function

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One of the most important inherited metabolic disorders is GM1 gangliosidosis, which is a progressive neurological disorder. The main cause of this disease is a genetic defect in the enzyme β‐galactosidase due to a mutation in the glb1 gene. Lack of this enzyme in cells (especially neurons) leads to the accumulation of ganglioside substrate in nerve tissues, followed by three clinical forms of GM1 disease (neonatal, juvenile, and adult variants). Genetically, many mutations occur in the exons of the glb1 gene, such as exons 2, 6, 15, and 16, so the most common ones reported in scientific studies include missense/nonsense mutations. Therefore, many studies have examined the genotype‐phenotype relationships of this disease and subsequently using gene therapy techniques have been able to reduce the complications of the disease and alleviate the signs and symptoms of the disease. In this regard, the present article reviews the general features of GM1 gangliosidosis and its mutations, as well as gene therapy studies and animal and human models of the disease.

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Lysosomal storage diseases: current therapies and future alternatives

et al. 2020

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Comprehensive behavioral and biochemical outcomes of novel murine models of GM1-gangliosidosis and Morquio syndrome type B

Cited by 26 publications

References 49 publications

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Gene therapy approaches for GM1 gangliosidosis: Focus on animal and cellular studies

Lysosomal storage diseases: current therapies and future alternatives

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