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Disruptions in brain sphingolipid metabolism reveal new insights into cause of Gaucher disease

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A study by researchers at Baylor College of Medicine, Jan and the Dan Duncan Neurological Research Institute at Texas Children’s Hospital and a collaboration of institutions is the first to link neuronal activity to levels of sphingolipids, a type of fat, in brain cells. Furthermore, disruption of sphingolipid metabolism results in severe physical damage and neurodegeneration in the animal species, revealing a new genetic perspective to the cause of Gaucher’s disease. Published in Scientific ProgressThe project provides an opportunity for new therapeutic approaches for this and other neurodegenerative diseases.

“Neurodegenerative diseases affect millions of people worldwide. Research on these conditions focuses mainly on conflicts in protein metabolism. or the breakdown of sphingolipids — and they contribute significantly to the development of neuronal toxins. human genes at Baylor and researcher and chair in neurogenetics at Jan and Dan Duncan Neurological Research Institute at Texas Children’s.

“This is a breakthrough study that has uncovered many unknowns about how sphingolipids are managed,” Bellen said. “It explains the close relationship between glycosphingolipid metabolism and rare and common environmental conditions. In addition, it provides valuable insights into Gaucher’s disease that opens up ways to improve therapies for this and many other neurodegenerative diseases, including. Parkinson’s disease. “

The accumulation of glucosylceramide causes Gaucher’s disease

Proteins and lipids are broken down by enzymes in the internal structure or organs called lysosomes, which act as compactors of cellular waste or recycling centers. Any disturbance in this purification process allows waste products to accumulate in the lysosomes, which can lead to the development of neurons, Brain cells which is particularly vulnerable to lysosomal dysfunction.

Gaucher’s disease is a rare and lysosomal storage disorder that affects nearly 6,000 people in the United States. These individuals have mutations in Glucosylceramides Beta (GBA1) that secrete the enzyme glucocerebrosidase that results in the conversion of sphingolipid called glucosylceramide (GlcCer) to ceramide. In the absence of this enzyme, GlcCer accumulates in other organs including the brain, liver, bones and saifa.

Neuronal activity leads to the production of glucosylceramide

Dr. Liping Wang, a Ph.D. graduate, said: “To ridicule the improved genetic makeup of the GlcCer collection we conducted a thorough study on the Gba1b gene, the GBA1 gene. in the Bellen lab and the first author of the study. ”Interestingly, we found that in normal conditions, the proteins associated with this cell are expressed only in glia. We later found that also in normal conditions, neurons bind to GlcCer using ceramide glucosyltransferase, an enzyme secreted by GlcT. GlcCer is also broken. down to ceramide by an enzyme that Gba1b is secreted into the glia. Therefore, GlcCer requires transport from neurons to glia to decompose. “

Researchers have explored this way of life in the eyes of fruit, an improved process for studying neurodegeneration. The visual acuity of flies consists of hundreds of structural features called ommatidia, which have eight optical nerves arranged in a circular pattern surrounded by color and cone. glial cells. This process supports the structure and vascular function of the photoreceptor. Using a cultural system with the monitoring of the movement of light-sensitive GlcCer, the group showed that GlcCer is transported from neurons to glia.

To assess how Gba1b cell loss causes damage and damage in neurons and glia, Liping and its colleagues induced flies that do not have Gba1b cells. First, they showed that Gba1b is needed in the glia and is sufficient to support neuronal function. Liping then examined the location and levels of the components of Gba1b, GlcCer in the flywheel by exposing large insects to a 12-hour darkness / light cycle. ” GlcCer levels both in neurons and in glia pigment, ”Liping said. “We have noticed a similar increase in GlcCer levels in different parts of the brain, shows this neuronal function results in GlcCer integration in the central nervous system, which is an interesting discovery. This is the first study to link neuronal activity to sphingolipid levels.

Gba1b in the glia supports the activity of neurons nearby and regulates GlcCer levels

The researchers noted that the loss of Gba1b results in a significant increase in lysosomes in the glia with the continued accumulation of GlcCer in these cells and the symptoms of glial symptoms followed by neurodegeneration. Also, they found a blood thinner known as White enhances GlcCer transport to glial lysosomes. Their data suggest that while GlcCer concentrations are toxic in two cell types, the structure and function of glia is affected primarily and this is followed by loss of neurons function.

Finally, they found that the protein signaling pathway in glial cells called alteration of growth-beta / morphogenetic bones (TGF-beta / BMP) results in the transfer of GlcCer from neurons to glia through small structures called exosomes. Bellen’s team also confirmed that cell lines derived from human tissues use similar mechanisms to regulate sphingolipid levels.

Together, these new case studies provide a comprehensive first indication of how neuronal functions and interactions between neurons and glia balance sphingolipid and ceramide metabolism to contribute to Gaucher disease. “This also has implications for many other neurodegenerative conditions including lysosomal storage disorders and Parkinson’s disease,” Bellen said. “We are happy with the possibility of an attack on the roads they have planned lipid metabolism which could lead to improved treatment for patients suffering from these conditions. “

Other participants in the study included Guang Lin, Zhongyuan Zuo, Yarong Li, Seul Kee Byeon, Akhilesh Pandey. They are affiliated with one or more of the following institutions: Baylor College of Science, Jan and Dan Duncan Center for Neurological Research, Texas Children’s Hospital, Mayo Clinic and Manipal Academy of Higher Education.


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Learn more:
Liping Wang et al, Neuronal activity results in glucosylceramide secreted by exosomes to lysosomal damage in the glia, Scientific Progress (2022). DOI: 10.1126 / sciadv.abn3326. www.science.org/doi/10.1126/sciadv.abn3326

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