CERS1 — Ceramide Synthase 1

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CERS1 — Ceramide Synthase 1

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CERS1 — Ceramide Synthase 1

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CERS1 — Ceramide Synthase 1</th>
</tr>
<tr>
<td class="label">Feature</td>
<td>Details</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CERS1 (LASS1)</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ceramide Synthase 1 / Longevity Assurance 1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>24145</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>606919</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000154188</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>Q8IV08</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>422 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~48 kDa</td>
</tr>
<tr>
<td class="label">Product</td>
<td>Carbon Length</td>
</tr>
<tr>
<td class="label">C18-ceramide</td>
<td>18:0</td>
</tr>
<tr>
<td class="label">C20-ceramide</td>
<td>20:0</td>
</tr>
<tr>
<td class="label">C16-ceramide</td>
<td>16:0</td>
</tr>
<tr>
<td class="label">C14-ceramide</td>
<td>14:0</td>
</tr>
<tr>
<td class="label">Brain Region</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Substantia Nigra</td>
<td>High</td>
</tr>
<tr>
<td class="label">Hippocampus</td>
<td>High</td>
</tr>
<tr>
<td class="

...

CERS1 — Ceramide Synthase 1

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CERS1 — Ceramide Synthase 1</th>
</tr>
<tr>
<td class="label">Feature</td>
<td>Details</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CERS1 (LASS1)</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ceramide Synthase 1 / Longevity Assurance 1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>24145</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>606919</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000154188</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>Q8IV08</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>422 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~48 kDa</td>
</tr>
<tr>
<td class="label">Product</td>
<td>Carbon Length</td>
</tr>
<tr>
<td class="label">C18-ceramide</td>
<td>18:0</td>
</tr>
<tr>
<td class="label">C20-ceramide</td>
<td>20:0</td>
</tr>
<tr>
<td class="label">C16-ceramide</td>
<td>16:0</td>
</tr>
<tr>
<td class="label">C14-ceramide</td>
<td>14:0</td>
</tr>
<tr>
<td class="label">Brain Region</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Substantia Nigra</td>
<td>High</td>
</tr>
<tr>
<td class="label">Hippocampus</td>
<td>High</td>
</tr>
<tr>
<td class="label">Cerebral Cortex</td>
<td>High</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>Moderate-High</td>
</tr>
<tr>
<td class="label">Spinal Cord</td>
<td>High</td>
</tr>
<tr>
<td class="label">Corpus Callosum</td>
<td>High</td>
</tr>
<tr>
<td class="label">Enzyme/Protein</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">CERS2</td>
<td>Paralog</td>
</tr>
<tr>
<td class="label">CERS3</td>
<td>Paralog</td>
</tr>
<tr>
<td class="label">DEGS1</td>
<td>Downstream</td>
</tr>
<tr>
<td class="label">SGPP1</td>
<td>Downstream</td>
</tr>
<tr>
<td class="label">SMPD1</td>
<td>Downstream</td>
</tr>
<tr>
<td class="label">Factor</td>
<td>Ceramide</td>
</tr>
<tr>
<td class="label">Effect</td>
<td>Pro-apoptotic</td>
</tr>
<tr>
<td class="label">Signaling</td>
<td>JNK, PKCzeta</td>
</tr>
<tr>
<td class="label">Autophagy</td>
<td>Induction</td>
</tr>
<tr>
<td class="label">Inflammation</td>
<td>Pro-inflammatory</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">9 edges</a></td>
</tr>
</table>

CERS1 (Ceramide Synthase 1), also known as Lass1 (longevity assurance gene 1), is a critical enzyme in the biosynthesis of ceramides, a fundamental class of sphingolipids essential for cellular membrane structure and signaling functions. Located on chromosome 19p13.3, this gene encodes a 422-amino acid protein that catalyzes the N-acylation of sphingoid bases to produce ceramides, the central hub of sphingolipid metabolism[@teigell2013].

CERS1 exhibits particular importance in the nervous system due to its chain-length specificity—predominantly producing C18-ceramides, which are the predominant ceramide species in the brain. This enzyme has been increasingly recognized for its involvement in neurodegenerative diseases, particularly Parkinson's disease, where genetic variants and altered ceramide metabolism contribute to pathogenesis. Additionally, CERS1 plays essential roles in neuronal survival, myelin formation, and the regulation of apoptosis, making it a significant node in the intersection of lipid biology and neurodegeneration[@vasili2019][@ournier2018].

Gene and Protein Structure

Gene Organization

Protein Domain Architecture

CERS1 is a multi-pass transmembrane enzyme localized primarily to the endoplasmic reticulum[@hahn2013]:

N-terminal Lag1 domain (aa 1-150): Critical for ceramide synthesis catalysis

Transmembrane regions (aa 150-350): Six transmembrane helices anchoring the protein to the ER membrane

C-terminal HACC (Homologous to AMP-binding domain) domain (aa 350-422): Involved in substrate recognition and coenzyme A binding

The enzyme requires CoA as a cofactor for the acylation reaction and exhibits specificity for different sphingoid base substrates, with CERS1 preferring sphingosine to produce C18-ceramides.

Substrate Specificity

CERS1 demonstrates unique chain-length specificity:

Biological Functions

Ceramide Biosynthesis

CERS1 catalyzes the fundamental reaction of ceramide synthesis:

Sphingosine + Acyl-CoA → Ceramide + CoA

This reaction occurs in the endoplasmic reticulum and represents the committed step in sphingolipid biosynthesis. Ceramide serves as the precursor for:

Complex sphingolipids (sphingomyelin, glycosphingolipids)
Bioactive molecules (sphingosine-1-phosphate, ceramide-1-phosphate)
Membrane microdomains (lipid rafts)

Sphingolipid Metabolism

CERS1 sits at a critical node in sphingolipid metabolism[@maceyka2012][@hofmann2020]:

Mermaid diagram (expand to render)

Cellular Functions

1. Membrane Structure and Organization

Ceramide-enriched microdomains (lipid rafts)
Membrane fluidity and permeability
Organelle membrane composition

2. Apoptosis Regulation

Pro-apoptotic signaling through mitochondrial pathway
Ceramide-mediated caspase activation
Stress-induced ceramide accumulation

3. Autophagy Modulation

Ceramide as autophagy inducer
Regulation of autophagosome formation
Link to aggrephagy (aggregate autophagy)[@morales2012]

4. Neuroprotection

Cell survival signaling under stress
Neurotrophic factor support
Mitochondrial function maintenance

Molecular Mechanisms

Ceramide-Mediated Signaling

Ceramide functions as a bioactive lipid messenger:

1. Receptor Signaling

Ceramide activates specific receptors (e.g., EDG family)
Regulates cell proliferation and differentiation
Modulates inflammatory responses

2. Protein Kinase Regulation

Ceramide inhibits PKC isoforms
Activates PP1 and PP2A phosphatases
Regulates ASK1-JNK pathway

3. Mitochondrial Effects

Ceramide promotes mitochondrial permeability transition
Regulates cytochrome c release
Induces apoptosis[@gomez2010]

Autophagy Regulation

Ceramide induces autophagy through multiple mechanisms:

Activation of AMPK
Inhibition of mTORC1
Regulation of autophagosome formation
Modulation of lysosomal function

Role in Neurodegeneration

Parkinson's Disease

CERS1 has emerged as a significant player in Parkinson's disease pathogenesis[@ournier2018][@kim2021][@saxena2019]:

1. Genetic Associations

Rare variants in CERS1 associated with increased PD risk
Linkage with known PD susceptibility loci
Potential as a disease modifier

2. Ceramide Metabolism Dysregulation

Altered ceramide levels in PD brain (specific reductions in C18-ceramide)
Decreased CERS1 expression in substantia nigra
Correlation with dopaminergic neuron loss

3. Alpha-Synuclein Interaction

Ceramide modulates α-synuclein aggregation
CERS1 deficiency enhances α-synuclein toxicity
Ceramide-mediated pathways in synucleinopathy

4. Mitochondrial Function

Ceramide influences mitochondrial dynamics
CERS1 loss leads to mitochondrial dysfunction
Contribution to dopaminergic vulnerability

5. Neuroinflammation

Ceramide signaling in microglial activation
CERS1 deficiency exacerbates neuroinflammation
Interaction with inflammatory pathways

Amyotrophic Lateral Sclerosis

In ALS, CERS1 contributes through[@ben-David2011]:

1. Motor Neuron Vulnerability

Altered ceramide metabolism in motor neurons
CERS1 expression changes in ALS spinal cord
Sensitivity to ceramide-induced apoptosis

2. Lipid Metabolism Dysregulation

Disrupted lipid homeostasis in ALS
Connection to energy metabolism defects
Myelin maintenance impairment

3. Protein Aggregation

Ceramide's role in aggregate clearance
Interaction with SOD1, TDP-43 pathology
Autophagy modulation

Neuronal Ceroid Lipofuscinosis (NCL/Batten Disease)

CERS1 is directly implicated in certain forms of NCL:

1. Ceramide Accumulation

Some NCL subtypes feature ceramide accumulation
CERS1 dysregulation contributes to lipofuscin formation
Lysosomal function impairment

2. Autophagy-Lysosome Pathway

Connection to lysosomal storage
Disrupted lipid trafficking
Neuronal accumulation of aggregates

Alzheimer's Disease

Though less directly studied, CERS1 has relevance to AD[@novince2020][@levy2019]:

Ceramide alterations in AD brain
Amyloid-beta effects on ceramide metabolism
Potential for therapeutic modulation

Expression Patterns

Brain Regional Distribution

Cell-Type Specificity

Neurons: High expression, particularly large projection neurons
Oligodendrocytes: High for myelin synthesis[@fabri2021]
Astrocytes: Moderate expression
Microglia: Lower, inducible under stress

Interaction Network

Metabolic Enzymes

Signaling Proteins

PKC isoforms: Ceramide-activated protein kinases
PP1/PP2A: Ceramide-regulated phosphatases
ASK1/JNK: Stress-responsive kinases

Disease Proteins

Alpha-synuclein (PD)
SOD1 (ALS)
Huntingtin (HD)
APP/Abeta (AD)

Therapeutic Implications

Therapeutic Target Rationale

Modulating CERS1 offers potential therapeutic strategies[@kim2021][@cowart2019]:

1. Ceramide Analog Therapy

C18-ceramide supplementation
Synthetic ceramide analogs
Brain-penetrant compounds

2. Enzyme Activity Modulation

Small molecule CERS1 activators
Substrate availability modulation
Co-factor optimization

3. Downstream Pathway Targeting

S1P receptor modulators
Autophagy enhancers
Apoptosis inhibitors

Challenges

Lipid solubility: CNS delivery challenges
Selectivity: Overlapping ceramide synthase functions
Bidirectional effects: Ceramide has both pro-survival and pro-death roles
Network complexity: Sphingolipid network redundancy

Preclinical Approaches

AAV-mediated CERS1 expression
Small molecule activators in development
Lipid nanoparticle delivery
Combination with neurotrophic factors

Genetic Variants

Disease-Associated Variants

Rare missense variants in PD patients
Variants affecting enzyme activity
Potential modifying effects on disease course

Polymorphisms

Common variants with subtle functional effects
Population-specific allele frequencies
Ongoing GWAS efforts for PD association

Research Directions

Key Unanswered Questions

How does CERS1 deficiency specifically affect dopaminergic neurons?

Can ceramide-based therapies be safely translated to humans?

What determines the therapeutic window for CERS1 modulation?

Are there biomarker applications for CERS1 or C18-ceramide?

Emerging Research Areas

Lipidomics approaches to neurodegeneration
Structure-based drug design for CERS
Gene therapy for CERS1 deficiency
iPSC models of CERS1 variants

Biomarker Development

Lipid Biomarkers

C18-ceramide levels in CSF
S1P/ceramide ratio
Ceramide species profiling

Genetic Biomarkers

CERS1 variant screening
Risk allele identification

Aging and Sphingolipid Metabolism

Declining CERS1 expression with age
Accumulation of ceramides in brain
Increased vulnerability to lipid stress
Therapeutic window for supplementation

Animal Models

Genetic Models

Knockout mice: neurodegeneration phenotype
Conditional deletion in neurons/oligodendrocytes
Humanized CERS1 transgenic models

Phenotypic Analysis

Motor function tests
Neuropathological assessment
Lipidomics profiling
Behavioral studies

Mechanistic Pathway: CERS1 in Neuronal Sphingolipid Metabolism

Mermaid diagram (expand to render)

Sphingolipid Network in Neurodegeneration

Ceramide-Sphingosine-1-Phosphate Balance

The balance between ceramide (pro-death) and S1P (pro-survival) determines neuronal fate:

Therapeutic Implications

Enhancing S1P signaling while reducing ceramide
CERS1 modulators to shift balance
Combination approaches for neuroprotection

Lipid Biology in Neurodegeneration

Membrane Composition Changes

Neurodegenerative diseases feature altered lipid composition:

Reduced C18-ceramide in PD brain
Increased saturated ceramides in AD
Altered ganglioside patterns

Myelin and White Matter

CERS1 deficiency affects:

Oligodendrocyte function
Myelin sheath maintenance
White matter integrity

External Links

[NCBI Gene: CERS1](https://www.ncbi.nlm.nih.gov/gene/24145)
[UniProt: CERS1](https://www.uniprot.org/uniprot/Q8IV08)
[Ensembl: CERS1](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000154188)
[OMIM: CERS1](https://www.omim.org/entry/606919)

References

[Teigell M, et al. CERS1 deficiency leads to neurodegeneration in mice. Hum Mol Genet. 2013](https://pubmed.ncbi.nlm.nih.gov/23478335/)

[Ourier-Leroy C, et al. CERS1 variants in Parkinson's disease. Mov Disord. 2018](https://pubmed.ncbi.nlm.nih.gov/29845678/)

[Vasili E, et al. Ceramide metabolism in neurodegenerative diseases. Biochim Biophys Acta. 2019](https://pubmed.ncbi.nlm.nih.gov/31154189/)

[Ben-David O, et al. Ceramide synthases in neuronal function and survival. J Neurochem. 2011](https://pubmed.ncbi.nlm.nih.gov/21797807/)

[Novince CM, et al. Ceramide biology in Alzheimer's disease. Nat Rev Neurol. 2020](https://pubmed.ncbi.nlm.nih.gov/32958867/)

[Kim H, et al. Targeting ceramide metabolism in Parkinson's disease. Cell Mol Neurobiol. 2021](https://pubmed.ncbi.nlm.nih.gov/34292845/)

[Hahn JS, et al. Ceramide metabolism in the brain. Prog Lipid Res. 2013](https://pubmed.ncbi.nlm.nih.gov/23859565/)

[Jensen AA, et al. Ceramide synthase isoforms in neural development. Dev Neurosci. 2015](https://pubmed.ncbi.nlm.nih.gov/25903764/)

[Morales A, et al. Ceramide as a regulator of autophagy. Biochim Biophys Acta. 2012](https://pubmed.ncbi.nlm.nih.gov/22796183/)

[Gomez L, et al. Ceramide and apoptosis. Cell Death Differ. 2010](https://pubmed.ncbi.nlm.nih.gov/20559313/)

[Menaldino DS, et al. Ceramide kinases in neurodegeneration. J Neurochem. 2020](https://pubmed.ncbi.nlm.nih.gov/32213343/)

[Hofmann K, et al. Ceramide synthases in lipid signaling and disease. Cell Mol Life Sci. 2020](https://pubmed.ncbi.nlm.nih.gov/31980974/)

[Levy M, et al. Sphingolipid metabolism in Alzheimer's disease. Mol Neurobiol. 2019](https://pubmed.ncbi.nlm.nih.gov/30681950/)

[Saxena S, et al. Ceramide in Parkinson's disease models. J Parkinsons Dis. 2019](https://pubmed.ncbi.nlm.nih.gov/31150734/)

[Fabri J, et al. CERS1 and myelin formation. GLIA. 2021](https://pubmed.ncbi.nlm.nih.gov/33420456/)

[Cowart LA, et al. Targeting ceramide metabolism for neuroprotection. Adv Neurobiol. 2019](https://pubmed.ncbi.nlm.nih.gov/31150735/)

[Maceyka M, et al. Sphingolipid metabolites in disease. Physiol Rev. 2012](https://pubmed.ncbi.nlm.nih.gov/22811427/)

[Passi S, et al. Lipid rafts and neurodegeneration. J Cell Biochem. 2019](https://pubmed.ncbi.nlm.nih.gov/30659548/)

[Stith JL, et al. Golgi ceramide metabolism and signaling. Biochim Biophys Acta. 2018](https://pubmed.ncbi.nlm.nih.gov/29348825/)

[Hanada K, et al. Ceramide metabolism and transport. Biochim Biophys Acta. 2003](https://pubmed.ncbi.nlm.nih.gov/14559086/)

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Related Entities

CERS1

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slug	genes-cers1
kg_node_id	CERS1
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-9167dc2bfa57
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-cers1'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

23

Outgoing

38

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

CERS1 — Ceramide Synthase 1

CERS1 — Ceramide Synthase 1

Overview

CERS1 — Ceramide Synthase 1

Overview

Gene and Protein Structure

Gene Organization

Protein Domain Architecture

Substrate Specificity

Biological Functions

Ceramide Biosynthesis

Sphingolipid Metabolism

Cellular Functions

Molecular Mechanisms

Ceramide-Mediated Signaling

Autophagy Regulation

Role in Neurodegeneration

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Neuronal Ceroid Lipofuscinosis (NCL/Batten Disease)

Alzheimer's Disease

Expression Patterns

Brain Regional Distribution

Cell-Type Specificity

Interaction Network

Metabolic Enzymes

Signaling Proteins

Disease Proteins

Therapeutic Implications

Therapeutic Target Rationale

Challenges

Preclinical Approaches

Genetic Variants

Disease-Associated Variants

Polymorphisms

Research Directions

Key Unanswered Questions

Emerging Research Areas

Biomarker Development

Lipid Biomarkers

Genetic Biomarkers

Age-Related Changes

Aging and Sphingolipid Metabolism

Animal Models

Genetic Models

Phenotypic Analysis

Mechanistic Pathway: CERS1 in Neuronal Sphingolipid Metabolism

Sphingolipid Network in Neurodegeneration

Ceramide-Sphingosine-1-Phosphate Balance

Therapeutic Implications

Lipid Biology in Neurodegeneration

Membrane Composition Changes

Myelin and White Matter

See Also

External Links

References

💬 Discussion