Nat Med: Excessive sphingolipid synthesis can cause amyotrophic lateral sclerosis in children

Amyotrophic lateral sclerosis (ALS) is a sporadic or hereditary progressive neurodegenerative disease.
The age of onset, motor neuron degeneration pattern and disease progression of ALS patients vary greatly.

Amyotrophic lateral sclerosis (ALS) is a sporadic or hereditary progressive neurodegenerative disease.
The age of onset, motor neuron degeneration pattern and disease progression of ALS patients vary greatly.
Amyotrophic lateral sclerosis (ALS) is a sporadic or hereditary progressive neurodegenerative disease.
The age of onset, motor neuron degeneration pattern and disease progression of ALS patients vary greatly.

In addition to the more common sporadic ALS that usually occurs between 55 and 75 years of age, having a single-gene genetic pathogenic mutation is a basic feature of an increasing number of familial and early-onset ALS cases.
It can provide unique mechanisms and pathophysiological insights for diseases, and can guide the formulation of reasonable treatment strategies.

Although the pathogenesis of ALS involves a variety of cellular processes, so far no correlation between single-gene metabolic disorders and ALS has been found.

In this study, the researchers found that SPTLC1 mutants, which can lead to unrestricted sphingolipid synthesis, induce single-gene mutant ALS.

The researchers identified four specific, dominant SPTLC1 mutants in seven families with childhood ALS.

SPTLC1 mutation information in children with ALS

SPTLC1 mutation information in children with ALS

These mutations disrupted the normal steady-state regulation of SPT (serine palmitoyl transferase) by ORMDL protein, resulting in unregulated SPT activity and increased levels of classic SPT products.
It is worth noting that by comparing the formation of SPTLC1 mutants, the researchers found that the conversion of the amino acid altered by SPT from serine to alanine would lead to an increase in the level of deoxysphingolipids and manifested as hereditary sensory and autonomic neuropathy.
Alternative phenotype.

The conversion of the amino acid altered by SPT from serine to alanine leads to an increase in the level of deoxysphingolipids and manifests as an alternative phenotype of hereditary sensory and autonomic neuropathy.
The conversion of the amino acid altered by SPT from serine to alanine leads to an increase in the level of deoxysphingolipids and manifests as an alternative phenotype of hereditary sensory and autonomic neuropathy.

Researchers used small interfering RNA to selectively target and degrade the ALS allele of SPTLC1, which can maintain the integrity of the normal allele and normalize the level of sphingolipids in vitro.

The role of primary metabolic disorders in ALS is still unknown.

ORMDL protein-mediated regulation of SPT homeostasis

ORMDL protein-mediated regulation of SPT homeostasis

In summary, the results of the study reveal that excessive sphingolipid biosynthesis may be related to the pathogenesis of motor neuron-related diseases.

The results of this study revealed that excessive sphingolipid biosynthesis may be related to the pathogenesis of motor neuron-related diseases.
The results of this study revealed that excessive sphingolipid biosynthesis may be related to the pathogenesis of motor neuron-related diseases.

Original source:

Mohassel, P.

, Donkervoort, S.
, Lone, MA et al.

Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.

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