A new study is the first to associate neuronal activity to the levels of sphingolipids, a type of fat, in brain cells. Furthermore, disruption of sphingolipid metabolism led to significant neuronal damage and neurodegeneration in animal models, revealing a new molecular perspective to the cause of Gaucher’s disease. Published in Science Advances, the work offers novel opportunities to develop therapies for this and other neurodegenerative disorders.
“Neurodegenerative disorders affect millions worldwide. Research on these conditions has largely focused on perturbations in protein metabolism. However, there is emerging evidence that disruptions in lipid metabolism – particularly those that perturb the synthesis or breakdown of sphingolipids – also contribute significantly to the progressive neuronal toxicity observed in neurodegeneration,” said corresponding author.
“This is a path-breaking study that has uncovered many previously unknown aspects of how sphingolipids are regulated,” the author said. “It has revealed a close relationship between glycosphingolipid metabolism and rare as well as common neurological conditions. Moreover, it offers valuable insights into the molecular cause of Gaucher disease that has opened possible avenues to develop potential therapies for this and several other neurodegenerative disorders, including Parkinson’s disease.”
Proteins and lipids are broken down by enzymes in intracellular structures or organelles called lysosomes, which serve as cellular trash compactors or recycling centers. Any perturbations in this cleanup process allows metabolic waste products to accumulate in the lysosomes, which can cause a progressive degeneration of neurons, brain cells that are particularly vulnerable to lysosomal dysfunction.
Gaucher disease is a rare metabolic and lysosomal storage disorder that affects approximately 6,000 individuals in the United States. These individuals have a mutation in the Glucosylceramides Beta (GBA1) gene that encodes the enzyme glucocerebrosidase that catalyzes the conversion of a sphingolipid called glucosylceramide (GlcCer) to ceramide. In the absence of this enzyme, GlcCer accumulates in various organs including the brain, liver, bone marrow and spleen.
“To tease apart the precise molecular mechanisms underlying GlcCer accumulation we undertook a detailed analysis of the Gba1b gene, the fly homolog of the human GBA1 gene,” said the first author of the study. “Interestingly, we found that under normal conditions, the protein encoded by this gene is expressed exclusively in glia. We then found that also under normal conditions, neurons synthesize GlcCer using ceramide glucosyltransferase, an enzyme that is encoded by GlcT. GlcCer is then broken down into ceramide by the enzyme encoded by Gba1b in glia. Hence, GlcCer needs to be transported from neurons to glia for degradation.”
The researchers investigated this metabolic path in fruit fly eyes, a well-established model to study neurodegeneration. The visual system of the flies consists of hundreds of highly organized structures called ommatidia, which have eight photoreceptor neurons arranged in a circular fashion surrounded by pigment and cone glial cells. This arrangement supports the structure and function of photoreceptor neurons. Using a co-culture system and monitoring the movement of fluorescently-labeled GlcCer, the team showed that GlcCer is transported from neurons to glia.
To assess how the loss of Gba1b gene leads to morphological and functional defects in the neurons and glia, the authors generated flies that lacked the Gba1b gene. First, they showed that Gba1b is required in glia and is sufficient to support neuronal function. They then examined the localization and levels of Gba1b’s substrate, GlcCer in the fly eye by exposing adult flies to a 12-hour dark/light cycle.
“In normal flies, light stimulation promoted a strong increase in the levels of GlcCer both in neurons and in the pigment glia,” the author said. “We observed similar increases in GlcCer levels in various parts of the brain, indicating that neuronal activity triggers GlcCer synthesis in the central nervous system, which is an exciting finding. This is the first study to associate neuronal activity to sphingolipid levels.”
The researchers observed that loss of Gba1b leads to a vast increase in lysosomes in the glia along with progressive accumulation of GlcCer in these cells and obvious signs of a glial demise followed by neurodegeneration. Moreover, they found a transmembrane transporter known as White promotes the transport of GlcCer to glial lysosomes. Their data suggest that while GlcCer accumulation is toxic in both cell types, the structure and function of glia are impacted first and this is followed by the functional loss of neurons.
Finally, they discovered that the protein signaling pathway in the glial cells called the transforming growth factor-beta/bone morphogenetic (TGF-beta/BMP) induces the transport of GlcCer from neurons to glia via small structures called exosomes. The Bellen team also verified that cell lines derived from human tissues employ similar mechanisms to regulate sphingolipid levels.
Together, these novel findings provide the first comprehensive demonstration of how neuronal activity and a cross-talk between neurons and glia regulate sphingolipid and ceramide metabolism to contribute to Gaucher’s disease. “This has also implications for several other neurodegenerative conditions including lysosomal storage disorders and Parkinson’s disease,” the senior author said. “We are excited by the possibility of targeting pathways that regulate lipid metabolism that can result in more effective treatments for patients suffering from these conditions.”
https://www.science.org/doi/10.1126/sciadv.abn3326
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fneuronal-activity_4&filter=22
How neuronal activity induces lysosomal degradation in glia
- 928 views
- Added
Latest News
How molecules in a cell int…
By newseditor
Posted 02 Dec
Genetic programmes underlie…
By newseditor
Posted 01 Dec
APOE variant neurons releas…
By newseditor
Posted 01 Dec
Reducing vitamin B5 slows b…
By newseditor
Posted 01 Dec
Mouse brain is 'rewired' du…
By newseditor
Posted 01 Dec
Other Top Stories
First patient-derived tumoroid model for cervical cancer
Read more
Distinct types of pulmonary neuroendocrine cells (PNECs) involved…
Read more
Origin of neuronal diversity in hypothalamus
Read more
Glial enriched stem cell progenitors repair functional deficits due…
Read more
The human uterine organoid that secrets uterine fluid developed!
Read more
Protocols
Temporally multiplexed imag…
By newseditor
Posted 02 Dec
Efficient elimination of ME…
By newseditor
Posted 01 Dec
Personalized drug screening…
By newseditor
Posted 30 Nov
Multi-chamber cardioids unr…
By newseditor
Posted 29 Nov
Microfluidic-based skin-on-…
By newseditor
Posted 28 Nov
Publications
APOE4-promoted gliosis and…
By newseditor
Posted 01 Dec
Sensory neuronal STAT3 is c…
By newseditor
Posted 01 Dec
Vitamin B5 supports MYC onc…
By newseditor
Posted 01 Dec
Longitudinal evolution of d…
By newseditor
Posted 01 Dec
Pre-RNA splicing in metabol…
By newseditor
Posted 01 Dec
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar