Loss of Enzyme Activity in Mutated B4GALNT1 Gene Products in Patients with Hereditary Spastic Paraplegia Results in Relatively Mild Neurological Disorders: Similarity with Phenotypes of B4galnt1 Knockout Mice

Bhuiyan, Robiul H.; Ohmi, Yuhsuke; Ohkawa, Yuki; Zhang, Pu; Takano, Mariko; Hashimoto, Noboru; Okajima, Tetsuya; Furukawa, Koichi

doi:10.1016/j.neuroscience.2018.11.034

Cited by 31 publications

(38 citation statements)

References 38 publications

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“…Considering the clinical findings from these patients, loss of enzyme activity should be responsible for the clinical signs of HSP, whereas the intensity of their neurological disorders were milder than expected. These clinical features of the patients including male hypogonadism are very similar with abnormal phenotypes detected in B4galnt1 -deficient mice 75) as shown in Fig. 7.…”

Section: Abnormal Metabolism Of Gangliosides In Humansupporting

confidence: 80%

Elucidation of the enigma of glycosphingolipids in the regulation of inflammation and degeneration — Great progress over the last 70 years —

Furukawa

Ohmi

Bhuiyan

et al. 2019

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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Since globotetraosylceramide was defined as a major glycosphingolipid in human erythrocytes, various glycolipids have been found in normal cells and diseased organs. However, the implications of their polymorphic structures in the function of individual cells and tissues have not been clarified. Genetic manipulation of glycosphingolipids in cultured cells and experimental animals has enabled us to substantially elucidate their roles. In fact, great progress has been achieved in the last 70 years in revealing that glycolipids are essential in the maintenance of integrity of nervous tissues and other organs. Furthermore, the correct composition of glycosphingolipids has been shown to be critical for the protection against inflammation and degeneration. Here, we summarized historic information and current knowledge about glycosphingolipids, with a focus on their involvement in inflammation and degeneration. This topic is significant for understanding the biological responses to various stresses, because glycosphingolipids play roles in the interaction with various intrinsic and extrinsic factors. These findings are also important for the application of therapeutic interventions of various diseases.

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Section: Abnormal Metabolism Of Gangliosides In Humansupporting

confidence: 80%

Elucidation of the enigma of glycosphingolipids in the regulation of inflammation and degeneration — Great progress over the last 70 years —

Furukawa

Ohmi

Bhuiyan

et al. 2019

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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“…Loss-of-function mutations in the B4GALNT1 gene cause a block of ganglioside biosynthesis downstream of GM3 and GD3 (Bhuiyan et al, 2019) and increased GM3 levels (Harlalka et al, 2013), resulting in a complicated form of hereditary spastic paraplegia (HSP26). This suggests that GM3 cannot compensate for the lack of complex gangliosides.…”

Section: Diseases Resulting From Major Defects Of Ganglioside Biosyntmentioning

confidence: 99%

“…HSP26 is clinically characterized by spasticity of lower limbs and intellectual disability, which can be accompanied by cortical atrophy, peripheral neuropathy, psychiatric or endocrinological problems depending on the specific mutation inherited (Boukhris et al, 2013;Harlalka et al, 2013;Wakil et al, 2014). Mutations that partially preserve B4GALNT1 activity result in milder symptoms and later onset (Bhuiyan et al, 2019), suggesting a direct correlation between the extent of ganglioside reduction and disease severity. Demyelination, motor and sensory dysfunctions are likely the result of a disrupted interaction between MAG and the axonal gangliosides GD1a and GT1b, as these aspects of the disease are phenocopied in patients carrying MAG mutations (Novarino et al, 2014;Lossos et al, 2015;Roda et al, 2016).…”

Section: Diseases Resulting From Major Defects Of Ganglioside Biosyntmentioning

confidence: 99%

Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

et al. 2020

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Gangliosides are glycosphingolipids highly abundant in the nervous system, and carry most of the sialic acid residues in the brain. Gangliosides are enriched in cell membrane microdomains ("lipid rafts") and play important roles in the modulation of membrane proteins and ion channels, in cell signaling and in the communication among cells. The importance of gangliosides in the brain is highlighted by the fact that loss of function mutations in ganglioside biosynthetic enzymes result in severe neurodegenerative disorders, often characterized by very early or childhood onset. In addition, changes in the ganglioside profile (i.e., in the relative abundance of specific gangliosides) were reported in healthy aging and in common neurological conditions, including Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), stroke, multiple sclerosis and epilepsy. At least in HD, PD and in some forms of epilepsy, experimental evidence strongly suggests a potential role of gangliosides in disease pathogenesis and potential treatment. In this review, we will summarize ganglioside functions that are crucial to maintain brain health, we will review changes in ganglioside levels that occur in major neurological conditions and we will discuss their contribution to cellular dysfunctions and disease pathogenesis. Finally, we will review evidence of the beneficial roles exerted by gangliosides, GM1 in particular, in disease models and in clinical trials.

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“…Mice having B4galnt1 gene defects (B4galnt1(+/-) mice) show a partial deficiency of GM1 and are considered a model for Parkinson's disease (PD). The neurological symptoms are comparable to those in human patients with B4GALNT1 mutations [80]. The protein aggregation seen in these mice was successfully reduced by treatment with synthetic GM1 ganglioside, LIGA20, capable of crossing the blood-brain barrier (BBB) [81,82].…”

Section: Genetic Defects Of Glycosphingolipid Biosynthesismentioning

confidence: 63%

Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

Ryckman

Brockhausen

Walia

2020

IJMS

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Glycosphingolipids (GSLs) are a specialized class of membrane lipids composed of a ceramide backbone and a carbohydrate-rich head group. GSLs populate lipid rafts of the cell membrane of eukaryotic cells, and serve important cellular functions including control of cell–cell signaling, signal transduction and cell recognition. Of the hundreds of unique GSL structures, anionic gangliosides are the most heavily implicated in the pathogenesis of lysosomal storage diseases (LSDs) such as Tay-Sachs and Sandhoff disease. Each LSD is characterized by the accumulation of GSLs in the lysosomes of neurons, which negatively interact with other intracellular molecules to culminate in cell death. In this review, we summarize the biosynthesis and degradation pathways of GSLs, discuss how aberrant GSL metabolism contributes to key features of LSD pathophysiology, draw parallels between LSDs and neurodegenerative proteinopathies such as Alzheimer’s and Parkinson’s disease and lastly, discuss possible therapies for patients.

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Loss of Enzyme Activity in Mutated B4GALNT1 Gene Products in Patients with Hereditary Spastic Paraplegia Results in Relatively Mild Neurological Disorders: Similarity with Phenotypes of B4galnt1 Knockout Mice

Cited by 31 publications

References 38 publications

Elucidation of the enigma of glycosphingolipids in the regulation of inflammation and degeneration — Great progress over the last 70 years —

Elucidation of the enigma of glycosphingolipids in the regulation of inflammation and degeneration — Great progress over the last 70 years —

Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

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