Juvenile onset niemann-pick type C disease with refractory seizures

Kumawat, Banshi Lal; Saini, Pankaj; Sharma, C. M.; Sharma, Manisha; Manu, Lucian

doi:10.4103/aian.aian_292_19

Cited by 1 publication

(1 citation statement)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, directly measuring synaptic defects in the motor circuit may be critical to understanding NPC progression, because motor ataxia is a primary NPC symptom ( Patterson et al, 2020 ). Glutamatergic hyperexcitability may also underlie seizures ( Wu et al, 2022 ), another common NPC symptom ( Saini et al, 2019 ). Additionally, hyperexcitability has been linked to intellectual disability in other neurological disorders ( Liu et al, 2022 ) and could account for the intellectual disability in NPC patients ( Patterson et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Glycosphingolipids are linked to elevated neurotransmission and neurodegeneration in a Drosophila model of Niemann Pick type C

Eberwein,

Kulkarni,

Rushton

et al. 2023

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

The lipid storage disease Niemann Pick type C (NPC) causes neurodegeneration owing primarily to loss of NPC1. Here, we employed a Drosophila model to test links between glycosphingolipids, neurotransmission and neurodegeneration. We found that Npc1a nulls had elevated neurotransmission at the glutamatergic neuromuscular junction (NMJ), which was phenocopied in brainiac (brn) mutants, impairing mannosyl glucosylceramide (MacCer) glycosylation. Npc1a; brn double mutants had the same elevated synaptic transmission, suggesting that Npc1a and brn function within the same pathway. Glucosylceramide (GlcCer) synthase inhibition with miglustat prevented elevated neurotransmission in Npc1a and brn mutants, further suggesting epistasis. Synaptic MacCer did not accumulate in the NPC model, but GlcCer levels were increased, suggesting that GlcCer is responsible for the elevated synaptic transmission. Null Npc1a mutants had heightened neurodegeneration, but no significant motor neuron or glial cell death, indicating that dying cells are interneurons and that elevated neurotransmission precedes neurodegeneration. Glycosphingolipid synthesis mutants also had greatly heightened neurodegeneration, with similar neurodegeneration in Npc1a; brn double mutants, again suggesting that Npc1a and brn function in the same pathway. These findings indicate causal links between glycosphingolipid-dependent neurotransmission and neurodegeneration in this NPC disease model.

show abstract