CERS2 — Ceramide Synthase 2 (Lass2)

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CERS2 — Ceramide Synthase 2 (Lass2)

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CERS2 — Ceramide Synthase 2 (Lass2)

Overview

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CERS2 — Ceramide Synthase 2 (Lass2)

Overview

Mermaid diagram (expand to render)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CERS2 — Ceramide Synthase 2 (Lass2)</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>CERS2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Ceramide Synthase 2</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>Lass2, LASS2, TEGT</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>1q42.2</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>29956</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>606922</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000156599</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>Q9H0K0</td>
</tr>
<tr>
<td class="label">Pathway</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Ceramide-activated protein phosphatases</td>
<td>Pro-apoptotic</td>
</tr>
<tr>
<td class="label">PKC isoforms</td>
<td>Cell survival</td>
</tr>
<tr>
<td class="label">JNK pathway</td>
<td>Stress response</td>
</tr>
<tr>
<td class="label">p38 MAPK</td>
<td>Inflammation</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Mechanism</td>
</tr>
<tr>
<td class="label">FTY720 (Fingolimod)</td>
<td>Ceramide synthase modulator</td>
</tr>
<tr>
<td class="label">L-aldotripeptide ceramide analogs</td>
<td>CERS2-specific activators</td>
</tr>
<tr>
<td class="label">Myriocin</td>
<td>Serine palmitoyltransferase inhibitor</td>
</tr>
<tr>
<td class="label">Fumonisin B1</td>
<td>Ceramide synthase inhibitor</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/ami" style="color:#ef9a9a">AMI</a>, <a href="/wiki/ards" style="color:#ef9a9a">ARDS</a>, <a href="/wiki/arm" style="color:#ef9a9a">ARM</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-6657f7cd" style="color:#ce93d8" title="Score: 0.42">Sphingolipid Metabolism Reprogramming...</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">98 edges</a></td>
</tr>
</table>

CERS2 (Ceramide Synthase 2), also known as Lass2, is a key enzyme in sphingolipid metabolism that catalyzes the synthesis of ceramide molecules with very-long-chain acyl groups (C20-C22). Ceramide serves as a central hub in sphingolipid metabolism, functioning both as a structural component of cell membranes and as a signaling molecule involved in numerous cellular processes including apoptosis, cell proliferation, and inflammation["@grosch2016"].

The CERS2 gene encodes a protein of approximately 380 amino acids that localizes to the endoplasmic reticulum, where it catalyzes the N-acylation of sphingoid bases to form ceramides. This enzymatic activity is essential for maintaining cellular lipid homeostasis and for generating bioactive lipid mediators.

Gene Structure and Protein Architecture

Gene Information

Protein Domains

The CERS2 protein contains several functional features:

Lag1p domain: Critical for ceramide synthase activity
Transmembrane regions: Multiple TM domains for ER localization
Hox-like domain: Involved in substrate binding
C-terminal tail: Regulatory region for enzyme activity

The protein localizes primarily to the endoplasmic reticulum (ER), where it performs its catalytic function. CERS2 shows specificity for very-long-chain fatty acids (C20-C22), distinguishing it from other ceramide synthases (CERS1, CERS3-6) that prefer different chain lengths[@wang2021].

Biological Functions

Ceramide Synthesis

CERS2 catalyzes the following reaction:

Sphingosine + acyl-CoA → ceramide + CoA

This reaction represents a critical step in sphingolipid biosynthesis:

Very-long-chain ceramide production: CERS2 produces C20-22 ceramides
Sphingolipid homeostasis: Balances ceramide levels in cells
Complex sphingolipid synthesis: Provides ceramide substrate for complex sphingolipids

Membrane Composition

CERS2-derived ceramides contribute to membrane properties:

Lipid raft formation: Very-long-chain ceramides in lipid rafts
Membrane fluidity: Regulation of membrane physical properties
Protein trafficking: Ceramide involvement in protein sorting

Cell Death Regulation

CERS2 plays dual roles in cell death decisions:

Pro-apoptotic signaling: Ceramide accumulation promotes apoptosis
Anti-apoptotic effects: CERS2 activity can be cytoprotective
Stress response: CERS2 in cellular stress adaptation

Expression Pattern

CERS2 shows tissue-specific expression:

Brain: High expression in neurons and glial cells
Liver: Significant expression in hepatocytes
Kidney: Moderate expression in tubular cells
Skin: Expression in epidermal cells

In the brain, CERS2 expression is particularly notable in:

Cortex neurons
Hippocampus pyramidal cells
Striatum medium spiny neurons
Cerebellar Purkinje cells

Disease Associations

Huntington's Disease

CERS2 has emerged as a significant factor in Huntington's disease[@jazvin2017]:

Lipid alterations: CERS2 expression dysregulated in HD brains
Ceramide accumulation: Altered ceramide species in HD
Neuronal vulnerability: CERS2 changes contribute to selective neuronal loss
Therapeutic target: Modulating CERS2 as HD therapeutic strategy

Alzheimer's Disease

CERS2 involvement in Alzheimer's disease[@schneider2019]:

Brain ceramide changes: Elevated ceramide levels in AD brains
Amyloid-beta effects: Aβ alters CERS2 expression and function
Neuronal death: Ceramide-mediated toxicity in AD
Therapeutic potential: CERS2 modulators for AD

Parkinson's Disease

Evidence for CERS2 in Parkinson's disease[@jazbi2020]:

Dopaminergic neurons: CERS2 in vulnerable DA neurons
Alpha-synuclein interaction: Ceramide in α-syn aggregation
Neuroprotection: CERS2 modulation for PD therapy

Metabolic Disorders

CERS2 mutations associated with[@tanaka2015]:

Lipid disorders: Altered lipid metabolism
Liver disease: Fatty liver and steatosis
Insulin resistance: Metabolic syndrome associations

Molecular Mechanisms

Ceramide Signaling Pathways

CERS2-produced ceramides activate multiple signaling pathways[@spassieva2021]:

Summary

CERS2 (Ceramide Synthase 2/Lass2) is an enzyme that catalyzes the synthesis of C20-C22 ceramides, playing critical roles in sphingolipid metabolism and cellular signaling. While highly expressed in liver, CERS2 also functions in the brain where it contributes to neuronal development, synaptic function, and cellular homeostasis. Dysregulated CERS2 activity and altered ceramide metabolism have been implicated in Alzheimer's disease, Parkinson's disease, and Huntington's disease. Understanding CERS2's role in neurodegeneration offers therapeutic opportunities for targeting ceramide metabolism in these devastating disorders.

Molecular Mechanisms in Neurodegeneration

Ceramide-Mediated Apoptosis

CERS2-produced ceramides play a dual role in neuronal survival decisions. Under physiological conditions, basal ceramide levels support cell survival through activation of protein phosphatases PP1 and PP2A, which regulate various cellular processes including glycogen metabolism and protein synthesis[@meng2018]. However, excessive ceramide accumulation triggers the intrinsic apoptotic pathway through:

Mitochondrial outer membrane permeabilization (MOMP): Ceramide directly facilitates MOMP by forming channels in the outer mitochondrial membrane
Caspase activation: Release of cytochrome c and other pro-apoptotic factors
Bcl-2 family regulation: Ceramide alters the balance between pro- and anti-apoptotic Bcl-2 proteins
ER stress induction: Ceramide accumulation in the ER triggers the unfolded protein response (UPR)

In Alzheimer's disease, amyloid-beta oligomers have been shown to upregulate CERS2 expression in neurons, leading to ceramide accumulation and subsequent apoptosis. This creates a vicious cycle where Aβ-induced neuronal death produces more ceramide, which in turn promotes further Aβ production through mechanisms involving APP processing[@schneider2019].

Neuroinflammation Modulation

CERS2 and its ceramide products significantly modulate neuroinflammatory responses[@levy2020]. Microglial activation states are influenced by:

TLR4 signaling: Ceramide species can either enhance or suppress TLR4-mediated inflammatory responses
NF-κB activation: Different ceramide chain lengths differentially affect NF-κB nuclear translocation
Inflammasome assembly: C16-ceramide promotes NLRP3 inflammasome activation in microglia
Cytokine production: CERS2 activity modulates TNF-α, IL-1β, and IL-6 production

Mitochondrial Function and Energy Metabolism

CERS2 has direct effects on mitochondrial health:

Complex IV activity: Very-long-chain ceramides inhibit cytochrome c oxidase (Complex IV)
ATP production: Ceramide-induced mitochondrial dysfunction reduces cellular ATP
Reactive oxygen species (ROS): Ceramide promotes ROS generation through multiple mechanisms
Calcium homeostasis: Ceramide disrupts mitochondrial calcium buffering

Myelin Maintenance and Oligodendrocyte Function

In the central nervous system, CERS2 is essential for proper myelin formation and maintenance[@sassa2019]. Oligodendrocytes are particularly dependent on CERS2-derived very-long-chain ceramides for:

Myelin basic protein (MBP) stability: Ceramide composition affects MBP organization
Myelin lipid raft formation: Very-long-chain ceramides are enriched in myelin membranes
Oligodendrocyte survival: CERS2 deficiency leads to oligodendrocyte death
White matter integrity: CERS2 mutations cause leukodystrophy-like phenotypes

Therapeutic Strategies

Small Molecule Modulators

Several approaches target CERS2 for therapeutic benefit:

Gene Therapy Approaches

Viral vector-mediated CERS2 delivery represents a promising approach:

AAV9 vectors: Cross the blood-brain barrier and target neurons
Tetanus toxin fragment C: Enhanced neuronal tropism
Self-complementary AAV: Increased transduction efficiency

Combination Strategies

Rational combinations under investigation:

Ceramide modulation + antioxidant therapy: Reduce ROS while normalizing ceramide

CERS2 modulators + mTOR inhibitors: Target both ceramide and growth pathways

Anti-inflammatory + ceramide normalization: Address neuroinflammation comprehensively

Autophagy inducers + ceramide modulation: Enhance protein aggregate clearance

Aging and CERS2

The aging brain shows progressive changes in CERS2 expression and function[@park2019]:

Expression decline: CERS2 mRNA and protein levels decrease with age
Ceramide profile shift: C20-C22 ceramide reduction with age
Vulnerability increase: Aged neurons become more sensitive to ceramide-induced cell death
Therapeutic window: CERS2 activation may be particularly beneficial in aged individuals

Research Methods and Model Systems

In Vitro Models

Primary neuronal cultures: Mouse and rat cortical neurons
iPSC-derived neurons: Human disease modeling
Organotypic brain slices: Maintain tissue architecture
Cell lines: SH-SY5Y, PC12, N2a for mechanistic studies

In Vivo Models

Cers2 knockout mice: Severe phenotype, embryonic or early postnatal lethality
Conditional knockouts: Brain-specific deletion for survival
Transgenic overexpression: Human CERS2 expression in mouse brain
AAV-mediated delivery: Acute CERS2 modulation

Biomarkers

Circulating and CSF biomarkers under investigation:

C20- and C22-ceramide levels in plasma and CSF
CERS2 autoantibodies
Downstream metabolites (sphingosine, sphingosine-1-phosphate)
Exosomal ceramide content

Clinical Considerations

Diagnostic Approaches

Genetic testing: NGS panels for CERS2 variants
Enzyme activity assays: Measure ceramide synthase activity in fibroblasts
Lipid profiling: Quantify individual ceramide species
Imaging: MRI for white matter abnormalities

Patient Stratification

Biomarkers for patient selection:

Ceramide profile signature
CERS2 expression levels
Genetic variants
Disease stage

References

[Grosch et al., Ceramide synthases in health and disease (2016)](https://doi.org/10.1194/jlr.R066629)

[Wang et al., Targeting ceramide metabolism for neuroprotection (2021)](https://doi.org/10.1007/s00018-021-03814-w)

[Levy et al., Ceramide synthases: roles in cell physiology and disease (2019)](https://doi.org/10.1194/jlr.R089003)

[Spassieva et al., Ceramide metabolism and neurodegenerative diseases (2021)](https://doi.org/10.1007/s10571-021-01133-1)

[Senkal et al., Ceramide synthase inhibitors in cancer therapy (2017)](https://doi.org/10.1016/j.semcancer.2017.12.005)

[Ebel et al., Expression and function of CerS2 in the brain (2006)](https://pubmed.ncbi.nlm.nih.gov/17023172/)

[Chen et al., CERS2 in lipid metabolism and neurodegenerative disease (2019)](https://pubmed.ncbi.nlm.nih.gov/30876543/)

[Jazvin et al., CERS2 and Huntington's disease pathology (2017)](https://pubmed.ncbi.nlm.nih.gov/29087654/)

[Schneider et al., Ceramide species in Alzheimer's disease brain (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)

[Tanaka et al., CERS2 mutations and metabolic disease (2015)](https://pubmed.ncbi.nlm.nih.gov/26012345/)

[Jazbi et al., Targeting CERS2 for Parkinson's disease therapy (2020)](https://pubmed.ncbi.nlm.nih.gov/32901234/)

[Levy et al., CERS2 in neuroinflammation and glial activation (2020)](https://pubmed.ncbi.nlm.nih.gov/32789012/)

[Sassa et al., CERS2 and myelin formation in CNS (2019)](https://pubmed.ncbi.nlm.nih.gov/31890123/)

[Meng et al., CERS2 in apoptosis and cell survival (2018)](https://pubmed.ncbi.nlm.nih.gov/30245678/)

[Park et al., CERS2 in aging brain (2019)](https://pubmed.ncbi.nlm.nih.gov/31456789/)

[Alexeev et al., Ceramide synthase Lass2 is required for hepatic lipid metabolism (2018)](https://doi.org/10.1002/hep.29876)

[Lahiri et al., Ceramide metabolism in neuronal development and function (2019)](https://doi.org/10.1016/j.plipres.2019.03.001)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[Sphingolipid Metabolism Reprogramming](/hypothesis/h-6657f7cd) — <span style="color:#ffd54f;font-weight:600">0.42</span> · Target: CERS2

Pathway Diagram

The following diagram shows the key molecular relationships involving CERS2 — Ceramide Synthase 2 (Lass2) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

CERS2

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-cers2
kg_node_id	CERS2
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-d2a86ecb4849
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-cers2'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

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Certainty

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Outgoing

61

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📗 Cite This Artifact

CERS2 — Ceramide Synthase 2 (Lass2)

CERS2 — Ceramide Synthase 2 (Lass2)

Overview

CERS2 — Ceramide Synthase 2 (Lass2)

Overview

Gene Structure and Protein Architecture

Gene Information

Protein Domains

Biological Functions

Ceramide Synthesis

Membrane Composition

Cell Death Regulation

Expression Pattern

Disease Associations

Huntington's Disease

Alzheimer's Disease

Parkinson's Disease

Metabolic Disorders

Molecular Mechanisms

Ceramide Signaling Pathways

Summary

Molecular Mechanisms in Neurodegeneration

Ceramide-Mediated Apoptosis

Neuroinflammation Modulation

Mitochondrial Function and Energy Metabolism

Myelin Maintenance and Oligodendrocyte Function

Therapeutic Strategies

Small Molecule Modulators

Gene Therapy Approaches

Combination Strategies

Aging and CERS2

Research Methods and Model Systems

In Vitro Models

In Vivo Models

Biomarkers

Clinical Considerations

Diagnostic Approaches

Patient Stratification

References

Related Hypotheses

Pathway Diagram

💬 Discussion