Drosophila glia take shape to sculpt the nervous system

Corty, Megan M.; Coutinho-Budd, Jaeda

doi:10.1016/j.conb.2023.102689

Cited by 10 publications

(12 citation statements)

References 73 publications

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“…[62][63][64] In contrast, wrapping glia wrap the axons in peripheral nerves and function like Remak Schwann cells in mammals. 65 Recent studies indicate these cells are important for control of neuronal signalling speed and precision in Drosophila. 66 Whilst an evaluation of the peripheral nervous system has not been performed in MPS IIIC mice to our knowledge, a study 67 has reported substrate accumulation in Schwann cells in dorsal root ganglia and damage to the myelin sheath in spinal motor nerves in MPS IIIB mice with impaired tactile and thermal nociception also observed.…”

Section: Discussionmentioning

confidence: 99%

“…68 Astrocytes in Drosophila are similar both molecularly and morphologically to those in mammals and contribute towards neurotransmission. 65 Whilst the specific role of astrocytes in disease manifestation or propagation has not to our knowledge been specifically studied in Sanfilippo mouse models, an evaluation of the contribution that glia make to a similar disorder (Niemann-Pick C) suggested that astrocytes are not key to initiating or progressing disease pathology. 69 Further studies in Niemann-Pick C mice may be needed however, as the data in Zhang et al, 70 contradict those outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…They are critical for neuronal cell survival and function and reduced wrapping by cortical glia leads to impaired neuronal phagocytosis and impaired locomotion 62–64 . In contrast, wrapping glia wrap the axons in peripheral nerves and function like Remak Schwann cells in mammals 65 . Recent studies indicate these cells are important for control of neuronal signalling speed and precision in Drosophila 66 .…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, sub‐perineural (surface glia) and astrocytes (neuropil glia) appear implicated in the reduction in activity observed in MPS IIIC‐IR1 flies. Sub‐perineural glia along with perineural glia form the blood–brain and blood‐nerve barriers in flies, 65 enabling nutrient uptake and providing a barrier to passive diffusion into the nervous system, and it has previously been reported that blood–brain barrier is disturbed in MPS III 68 . Astrocytes in Drosophila are similar both molecularly and morphologically to those in mammals and contribute towards neurotransmission 65 .…”

Section: Discussionmentioning

confidence: 99%

“…Sub‐perineural glia along with perineural glia form the blood–brain and blood‐nerve barriers in flies, 65 enabling nutrient uptake and providing a barrier to passive diffusion into the nervous system, and it has previously been reported that blood–brain barrier is disturbed in MPS III 68 . Astrocytes in Drosophila are similar both molecularly and morphologically to those in mammals and contribute towards neurotransmission 65 . Whilst the specific role of astrocytes in disease manifestation or propagation has not to our knowledge been specifically studied in Sanfilippo mouse models, an evaluation of the contribution that glia make to a similar disorder (Niemann‐Pick C) suggested that astrocytes are not key to initiating or progressing disease pathology 69 .…”

Section: Discussionmentioning

confidence: 99%

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Drosophila melanogastermodels ofMPS IIIC(Hgsnat‐deficiency) highlight the role of glia in disease presentation

Hewson,

Choo,

Webber

et al. 2024

J of Inher Metab Disea

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Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III) is a recessively inherited neurodegenerative lysosomal storage disorder. Mutations in genes encoding enzymes in the heparan sulphate degradation pathway lead to the accumulation of partially degraded heparan sulphate, resulting ultimately in the development of neurological deficits. Mutations in the gene encoding the membrane protein heparan‐α‐glucosaminide N‐acetyltransferase (HGSNAT; EC2.3.1.78) cause MPS IIIC (OMIM#252930), typified by impaired cognition, sleep–wake cycle changes, hyperactivity and early death, often before adulthood. The precise disease mechanism that causes symptom emergence remains unknown, posing a significant challenge in the development of effective therapeutics. As HGSNAT is conserved in Drosophila melanogaster, we now describe the creation and characterisation of the first Drosophila models of MPS IIIC. Flies with either an endogenous insertion mutation or RNAi‐mediated knockdown of hgsnat were confirmed to have a reduced level of HGSNAT transcripts and age‐dependent accumulation of heparan sulphate leading to engorgement of the endo/lysosomal compartment. This resulted in abnormalities at the pre‐synapse, defective climbing and reduced overall activity. Altered circadian rhythms (shift in peak morning activity) were seen in hgsnat neuronal knockdown lines. Further, when hgsnat was knocked down in specific glial subsets (wrapping, cortical, astrocytes or subperineural glia), impaired climbing or reduced activity was noted, implying that hgsnat function in these specific glial subtypes contributes significantly to this behaviour and targeting treatments to these cell groups may be necessary to ameliorate or prevent symptom onset. These novel models of MPS IIIC provide critical research tools for delineating the key cellular pathways causal in the onset of neurodegeneration in this presently untreatable disorder.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Drosophila melanogastermodels ofMPS IIIC(Hgsnat‐deficiency) highlight the role of glia in disease presentation

Hewson,

Choo,

Webber

et al. 2024

J of Inher Metab Disea

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Glial overexpression of Tspo extends lifespan and protects against frataxin deficiency in Drosophila

Jullian,

Russi,

Turki

et al. 2024

Biochimie

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Loss of dihydroceramide desaturase drives neurodegeneration by disrupting endoplasmic reticulum and lipid droplet homeostasis in glial cells

Zhu,

Cho,

Lacin

et al. 2024

Preprint

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Dihydroceramide desaturases convert dihydroceramides to ceramides in the last step of thede novoceramide pathway. Reduction of DEGS1 dihydroceramide desaturase function in humans leads to the rare neurodegenerative disorder hypomyelinating leukodystrophy-18, but the exact mechanism that underlies the disease remains unclear. Through a forward genetic screen, we discovered thatinfertile crescent (ifc), the soleDrosophiladihydroceramide desaturase, governs central nervous system development and morphology. Expressed and genetically active most prominently in glia rather than neurons,ifcprimarily controls nervous system development through a cell autonomous function in glia. Within the nervous system, loss ofifcresults in ceramide depletion, dihydroceramide accumulation, and increased saturation of major membrane phospholipids. At the cellular level, loss ofifcleads to severe glial defects, particularly in cortex glia, including expansion of the endoplasmic reticulum, cell swelling, failure to enwrap neurons, and lipid droplet depletion. Our research supports a model in which inappropriate retention of dihydroceramide in the endoplasmic reticulum (ER) of glial cells drives ER expansion and cell swelling, disrupting glial function and leading to subsequent nervous system dysfunction. Given the conserved nature of thede novoceramide biosynthesis pathway, our findings in the fly system suggest that dihydroceramide-triggered expansion of the ER in the membrane-rich glial cells may be the proximal cause of hypomyelinating leukodystrophy-18 in humans.

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Drosophila glia take shape to sculpt the nervous system

Cited by 10 publications

References 73 publications

Drosophila melanogastermodels ofMPS IIIC(Hgsnat‐deficiency) highlight the role of glia in disease presentation

Drosophila melanogastermodels ofMPS IIIC(Hgsnat‐deficiency) highlight the role of glia in disease presentation

Glial overexpression of Tspo extends lifespan and protects against frataxin deficiency in Drosophila

Loss of dihydroceramide desaturase drives neurodegeneration by disrupting endoplasmic reticulum and lipid droplet homeostasis in glial cells

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