Loss of the Lysosomal Transporter SPNS1 in the Nervous System Causes Dysmyelination and White Matter Dysplasia

Core Concepts

Deletion of the lysosomal transporter SPNS1 in the nervous system leads to accumulation of lysophospholipids and sphingosine, resulting in dysmyelination, oligodendrocyte shedding, and white matter dysplasia.

Abstract

The study investigated the role of the lysosomal transporter SPNS1 in the central nervous system. Researchers generated nervous system-specific Spns1 knockout mice (Spns1flox/flox;nestin-Cre) and found that these mice exhibited severe neurological symptoms, growth retardation, and early mortality.
Key findings:

Deletion of Spns1 in the nervous system caused dysmyelination and white matter dysplasia due to the loss of oligodendrocytes during the lactation period.
Lipidomic analysis revealed accumulation of diverse lysophospholipid species and sphingosine in the brains of Spns1-deficient mice.
The levels of myelin glycolipids, such as galactosylceramide and sulfatide, were decreased in the white matter regions of Spns1 knockout mice.
Swollen and dysfunctional lysosomes accumulated in SPNS1-deficient cells and tissues, indicating that SPNS1 is indispensable for lysosomal integrity.
The results suggest that abnormal sphingosine metabolism due to the loss of SPNS1 leads to dysmyelination and white matter dysplasia, and that SPNS1 mutations may be involved in the pathogenesis of congenital cerebral white matter dysplasia in humans.

Stats

Spns1flox/flox mice showed significantly higher levels of myelin basic protein (MBP) compared to Spns1flox/flox;nestin-Cre mice.
The number of OLIG2-positive oligodendrocytes in the corpus callosum of Spns1flox/flox;nestin-Cre mice was significantly lower than that in control mice at postnatal day 18.
Levels of lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylinositol (LPI), and lysophosphatidylglycerol (LPG) were higher in the brains of Spns1flox/flox;nestin-Cre mice compared to controls.
Levels of ceramide, sphingomyelin, and sulfatide were decreased in the brains of Spns1flox/flox;nestin-Cre mice compared to controls.
Levels of sialic acid and its nucleotide CMP-N-acetyl neuraminic acid were significantly lower in the brains of Spns1flox/flox;nestin-Cre mice compared to controls.

Quotes

"Our data indicate that SPNS1 is indispensable for the metabolic pathway of specific lysophospholipids, whose loss makes oligodendrocytes vulnerable, and that SPNS1 is required for lysosomal function and integrity."
"Consistent with the results of lipidomic analysis of Spns1-deficient cultured cells, systemic Spns1-knockout embryos, and liver-specific Spns1-deficient mice, our lipidomic analysis of the brain of nervous system-specific Spns1-knockout mice revealed accumulation of lysophospholipids, including LPCs, LPEs, and LPIs."
"The results suggest that abnormal sphingosine metabolism due to the loss of SPNS1 leads to dysmyelination and white matter dysplasia, and that SPNS1 mutations may be involved in the pathogenesis of congenital cerebral white matter dysplasia in humans."

Key Insights Distilled From

Loss of SPNS1, a lysosomal transporter, in the nervous system causes dysmyelination and white matter dysplasia

by Ichimura,Y.,... at www.biorxiv.org 05-29-2024

https://www.biorxiv.org/content/10.1101/2024.05.29.596535v1

Deeper Inquiries

What are the potential therapeutic strategies to rescue the dysmyelination and white matter dysplasia phenotype in SPNS1-deficient mice?

In SPNS1-deficient mice, the dysmyelination and white matter dysplasia phenotype can potentially be rescued through several therapeutic strategies. One approach could involve targeting the lysosomal dysfunction caused by the loss of SPNS1. Enhancing lysosomal function through the use of lysosomal activators or modulators could help alleviate the accumulation of lysophospholipids and sphingosine, thereby restoring normal sphingolipid metabolism and myelin synthesis. Additionally, promoting oligodendrocyte survival and differentiation could be crucial in rescuing the myelination defects. This could be achieved through the administration of growth factors or small molecules that support oligodendrocyte maturation and myelin formation. Furthermore, gene therapy approaches aimed at restoring SPNS1 expression in the nervous system could potentially reverse the dysmyelination phenotype in SPNS1-deficient mice.

How do the specific accumulation patterns of lysophospholipids and depletion of myelin glycolipids in different brain regions contribute to the observed neurological symptoms in the SPNS1 knockout mice?

The specific accumulation patterns of lysophospholipids and depletion of myelin glycolipids in different brain regions play a significant role in the observed neurological symptoms in SPNS1 knockout mice. The accumulation of lysophospholipids, such as LPCs, LPEs, and LPIs, in regions like the olfactory bulb and hippocampus can disrupt normal neuronal function and signaling pathways. Lysophospholipids have been implicated in neuroinflammation, oxidative stress, and neuronal damage, which could contribute to the epilepsy and growth retardation seen in SPNS1-deficient mice. On the other hand, the depletion of myelin glycolipids, including ceramides, sphingomyelins, and sulfatides, in the white matter regions of the brain can directly impact myelin formation and maintenance. This depletion leads to dysmyelination and white matter dysplasia, resulting in impaired neuronal communication and neurological symptoms like epilepsy and growth retardation.

Given the role of SPNS1 in lysosomal function, how might other lysosomal storage disorders with neurological manifestations be related to SPNS1 dysfunction?

Other lysosomal storage disorders with neurological manifestations may be related to SPNS1 dysfunction through shared pathways and mechanisms involving lysosomal homeostasis and sphingolipid metabolism. SPNS1 plays a crucial role in lysosomal transport and sphingolipid metabolism, and its dysfunction can lead to lysosomal dysfunction and abnormal accumulation of lysophospholipids and sphingosine. Similarly, in lysosomal storage disorders, impaired lysosomal function results in the accumulation of undegraded substrates within lysosomes, leading to cellular dysfunction and tissue damage. The overlap in these pathogenic mechanisms suggests that SPNS1 dysfunction could contribute to or exacerbate the neurological manifestations seen in lysosomal storage disorders. Understanding the interplay between SPNS1 and lysosomal function in these disorders could provide insights into potential therapeutic targets for treating neurological symptoms associated with lysosomal storage disorders.