ATG10 Gene

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ATG10 Gene

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Pathway / Interaction Diagram

Overview

ATG10 (Autophagy Related 10) encodes an E2-like conjugating enzyme that plays an essential role in the autophagy conjugation system. This enzyme catalyzes the covalent attachment of ATG12 to ATG5, a critical step in autophagosome formation that is fundamental to cellular protein quality control and organelle clearance[^1][^2]. ATG10 is widely expressed in tissues throughout the body, with particularly important functions in neurons where autophagy is crucial for synaptic maintenance, mitochondrial quality control, and clearance of misfolded proteins[^3].

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Pathway / Interaction Diagram

Mermaid diagram (expand to render)

Overview

ATG10 (Autophagy Related 10) encodes an E2-like conjugating enzyme that plays an essential role in the autophagy conjugation system. This enzyme catalyzes the covalent attachment of ATG12 to ATG5, a critical step in autophagosome formation that is fundamental to cellular protein quality control and organelle clearance[^1][^2]. ATG10 is widely expressed in tissues throughout the body, with particularly important functions in neurons where autophagy is crucial for synaptic maintenance, mitochondrial quality control, and clearance of misfolded proteins[^3].

The autophagy pathway, mediated by ATG10 and related proteins, has emerged as a critical protective mechanism in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Dysregulation of ATG10-mediated autophagy contributes to the accumulation of protein aggregates that characterize these conditions[^4][^5]. Genetic variants in ATG10 have been associated with altered disease risk, making it both a biomarker and potential therapeutic target.

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Autophagy Related 10</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>ATG10</td></tr>
<tr><td><strong>Full Name</strong></td><td>Autophagy Related 10</td></tr>
<tr><td><strong>Chromosome</strong></td><td>5q21.3</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[94550](https://www.ncbi.nlm.nih.gov/gene/94550)</td></tr>
<tr><td><strong>OMIM</strong></td><td>610070</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000138107</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9Y4K0](https://www.uniprot.org/uniprot/Q9Y4K0)</td></tr>
<tr><td><strong>Protein Class</strong></td><td>E2 conjugating enzyme, autophagy</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Parkinson's Disease](/diseases/parkinsons-disease), [Alzheimer's Disease](/diseases/alzheimers-disease), ALS, Cancer</td></tr>
</table>
</div>

Gene Structure and Protein Architecture

Gene Organization

The human ATG10 gene is located on chromosome 5q21.3 and encodes a protein of 182 amino acids with a molecular weight of approximately 21 kDa. The gene consists of multiple exons and is conserved across eukaryotes, with orthologs in yeast (Atg10), mouse (Atg10), and other species[^1].

Protein Domains

The ATG10 protein possesses several key structural features:

E2 Enzyme Core Domain: The central portion of ATG10 contains the catalytic cysteine residue (Cys125 in humans) that forms a thioester intermediate with the C-terminal glycine of ATG12 during the conjugation reaction[^2].

ATG12 Binding Region: The N-terminal region mediates specific interaction with ATG12, the ubiquitin-like protein that ATG10 conjugates to ATG5.

ATG5 Interaction Surface: The C-terminal portion facilitates the transfer of ATG12 to ATG5, forming the ATG12-ATG5 conjugate.

Dimerization Domain: ATG10 can form homodimers, which may regulate its enzymatic activity and cellular localization[^6].

The Autophagy Conjugation System

The ATG12-ATG5 Conjugation Cascade

ATG10 functions within the canonical autophagy conjugation system:

ATG12 Activation: The E1-like enzyme ATG7 activates ATG12 by forming a thioester bond at its C-terminal glycine[^7].

ATG12 Transfer to ATG10: Activated ATG12 is transferred to the active site cysteine of ATG10 (E2 enzyme), forming an ATG10-ATG12 thioester intermediate[^2].

ATG12-ATG5 Conjugation: ATG10 catalyzes the formation of an isopeptide bond between the C-terminal glycine of ATG12 and a specific lysine residue (Lys130) in ATG5[^8].

Complex Formation: The ATG12-ATG5 conjugate non-covalently associates with ATG16L1 to form the ATG12-ATG5-ATG16L1 complex, which functions as an E3-like enzyme for LC3 lipidation.

Role in Autophagosome Biogenesis

The ATG12-ATG5-ATG16L1 complex is essential for autophagosome formation:

Isolation Membrane Recruitment: The complex localizes to the nascent isolation membrane (phagophore) and promotes its expansion.

LC3 Lipidation: The complex acts as an E3 enzyme for the lipidation of LC3 (MAP1LC3A), converting LC3-I to LC3-II[^9].

Autophagosome Closure: LC3-II mediates tethering and fusion events that lead to complete autophagosome formation.

Cargo Recognition: LC3-II on the inner autophagosomal membrane recognizes selective autophagy receptors.

Biological Functions of ATG10

Cellular Homeostasis

ATG10-mediated autophagy is essential for cellular homeostasis:

Protein Quality Control: Autophagy clears misfolded proteins and protein aggregates that accumulate during cellular stress[^4].

Organelle Turnover: Mitophagy (mitochondrial autophagy) removes damaged mitochondria through ATG10-dependent mechanisms.

Lipid Metabolism: Autophagy regulates lipid droplet mobilization and cellular lipid homeostasis.

ER Clearance: Autophagy participates in endoplasmic reticulum quality control through reticulophagy.

Neuronal Functions

In neurons, ATG10-mediated autophagy has specialized functions:

Synaptic Plasticity: Autophagy regulates synaptic vesicle turnover and dendritic spine morphology[^10].

Axonal Transport: Autophagosomes are transported along axons to deliver cargo to lysosomes.

Mitochondrial Quality Control: Neuronal mitochondria have high metabolic demands and require efficient quality control via mitophagy[^3].

Protein Aggregate Clearance: Neuronal autophagy must handle the high load of misfolded proteins associated with neurodegeneration.

Stress Response

ATG10 expression and activity are regulated by cellular stress:

Nutrient Deprivation: Starvation strongly induces autophagy through ATG10-dependent mechanisms[^1]
Oxidative Stress: Reactive oxygen species activate autophagy as a protective response
ER Stress: The unfolded protein response (UPR) intersects with autophagy pathways
Hypoxia: Hypoxic conditions induce ATG10 expression and autophagy

ATG10 in Alzheimer's Disease

Evidence of ATG10 Dysregulation in AD

Multiple studies have documented ATG10 alterations in Alzheimer's disease:

Expression Studies: ATG10 expression is reduced in AD brain tissue, particularly in vulnerable regions like the hippocampus and entorhinal cortex[^11].

AD Models: In cellular and animal models of AD, ATG10 levels correlate with amyloid-beta (Aβ) burden and neuronal viability[^5].

Genetic Associations: Polymorphisms in the ATG10 promoter region have been associated with AD risk in some populations[^12].

Mechanisms of ATG10 Dysfunction in AD

The relationship between ATG10 and AD pathology involves several mechanisms:

Autophagic Flux Impairment: Aβ accumulation impairs autophagic flux, reducing ATG10 effectiveness[^5].

Lysosomal Dysfunction: AD-related lysosomal abnormalities prevent proper autophagosome-lysosome fusion.

Protein Aggregation Load: Excessive Aβ and tau aggregates overwhelm the autophagy system.

Transcriptional Dysregulation: Transcription factors regulating ATG10 expression may be altered in AD.

Therapeutic Targeting of ATG10 in AD

Targeting ATG10 and the autophagy pathway represents a therapeutic strategy:

| Strategy | Approach | Status | References |
|----------|----------|--------|------------|
| ATG10 expression | Viral vector-mediated overexpression | Preclinical | [^13] |
| Autophagy enhancers | Rapamycin, trehalose | Clinical trials | [^14] |
| Small molecule activators | ATG10-specific activators | Research | [^15] |
| Gene therapy | AAV-ATG10 delivery | Research | [^13] |

Trehalose and rapamycin are autophagy inducers that have shown promise in AD models, though their effects involve multiple autophagy pathways beyond ATG10[^14].

ATG10 in Parkinson's Disease

ATG10 and Alpha-Synuclein Clearance

ATG10-mediated autophagy is particularly relevant to Parkinson's disease:

α-Synuclein Turnover: Autophagy, including the ATG12-ATG5 system, degrades α-synuclein aggregates[^16].

PD Models: In cellular models of α-synucleinopathy, ATG10 overexpression enhances aggregate clearance[^17].

Genetic Links: ATG10 polymorphisms have been associated with PD risk in some studies, though results vary by population[^18].

Mitophagy in PD

ATG10 participates in mitophagy, which is particularly relevant to PD:

Mitochondrial Dysfunction: PD is characterized by mitochondrial defects in dopaminergic neurons.

PINK1/Parkin Pathway: The canonical mitophagy pathway involves PINK1 and Parkin, with ATG10 providing supporting functions[^19].

Dopaminergic Neuron Vulnerability: Mitophagy defects may contribute to the selective vulnerability of dopaminergic neurons.

Therapeutic Implications

Targeting ATG10 in PD:

Aggregate Clearance: Enhancing ATG10 may improve α-synuclein clearance
Mitochondrial Health: ATG10-mediated mitophagy protects dopaminergic neurons
Neuroprotection: Combined approaches targeting multiple autophagy branches

ATG10 in ALS and Other Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis

ATG10 is implicated in ALS through protein aggregate clearance:

Protein Aggregates: ALS is characterized by cytoplasmic protein aggregates (TDP-43, SOD1, FUS).

Autophagy Activation: Enhancing autophagy, including ATG10-dependent pathways, may help clear aggregates.

Motor Neuron Vulnerability: Motor neurons rely on efficient autophagy due to their large size and high protein synthesis.

Huntington's Disease

In Huntington's disease:

Mutant huntingtin protein accumulates in aggregates
ATG10-mediated autophagy may help clear mutant huntingtin
Autophagy enhancers have shown promise in HD models

Prion Diseases

Prion diseases involve misfolded protein aggregates that may be cleared by autophagy:

ATG10 expression is altered in prion disease models
Autophagy enhancement may represent a therapeutic approach

Interaction Network

Core Autophagy Machinery

ATG10 interacts with the core autophagy proteins:

ATG7: The E1-like enzyme that activates ATG12 before transfer to ATG10[^7].

ATG12: The ubiquitin-like protein that ATG10 conjugates to ATG5[^2].

ATG5: The substrate receiving the ATG12 conjugate from ATG10[^8].

ATG16L1: Forms a complex with ATG12-ATG5 to create the E3-like complex[^9].

Regulatory Interactions

ATG10 activity is regulated by:

AMPK: Energy sensor that activates autophagy through mTOR inhibition.

mTOR: Negative regulator of autophagy; nutrient sufficiency suppresses ATG10 activity.

ULK1: Upstream kinase that initiates autophagy cascade.

Beclin 1: PI3K complex component that regulates autophagosome nucleation.

Disease-Specific Interactions

In neurodegeneration, ATG10 interacts with:

α-Synuclein: Selective autophagy receptor for aggregate clearance
Tau: Autophagy substrates in AD
APP/Aβ: Aβ accumulation affects autophagy
Mitochondrial Proteins: PINK1, Parkin in mitophagy

Expression Patterns

Tissue Distribution

ATG10 is ubiquitously expressed with highest levels in:

Brain (cortex, hippocampus, cerebellum)
Liver
Kidney
Heart muscle
Skeletal muscle

Cellular Localization

Subcellular: Cytosolic, with localization to autophagosomes
Cell Types: All cell types, with particular importance in neurons
Regional Expression: Neuronal subtypes show differential ATG10 expression

Brain Region Specificity

In the brain, ATG10 is expressed in:

Cortical neurons (all layers)
Hippocampal pyramidal neurons and granule cells
Cerebellar Purkinje cells
Substantia nigra dopaminergic neurons
Spinal cord motor neurons
Glial cells (astrocytes, microglia)

Genetic Variants and Disease Risk

ATG10 Polymorphisms

Several ATG10 variants have been studied:

Promoter Variants: rs1863889 and other promoter polymorphisms affect ATG10 expression[^12].

Coding Variants: Missense variants in the ATG10 coding region have been identified.

Association Studies: Mixed results for associations with AD and PD risk across populations.

Functional Implications

Genetic variants may affect:

ATG10 expression levels
Enzymatic activity
Protein stability
Autophagic flux

Therapeutic Strategies

Pharmacological Approaches

Several strategies target ATG10 and the autophagy pathway:

Autophagy Inducers:

Rapamycin: mTOR inhibitor, activates autophagy broadly[^14]
Trehalose: mTOR-independent autophagy enhancer[^14]
Lithium: Inositol monophosphatase inhibitor

ATG10-Specific Approaches:

Small molecule activators: Direct ATG10 activation (research phase)
Gene therapy: AAV-mediated ATG10 overexpression[^13]

Combination Strategies:

Autophagy enhancement with amyloid/tau-targeted approaches
Multi-target approaches for synergistic effects

Gene Therapy

AAV-mediated ATG10 delivery is being explored:

Local Delivery: Targeted injection to affected brain regions
Neuron-Specific Promoters: Ensuring expression in neurons
Controlled Expression: Regulated expression systems

Biomarker Potential

ATG10 and autophagy markers may serve as:

Biomarkers of autophagic activity in disease
Indicators of treatment response
Prognostic markers

Key Publications

Geng J, et al. (2008). "ATG10, an E2-like enzyme for ATG12 conjugation." Cell Cycle 7(20):2981-2986. PMID: 18669857(https://pubmed.ncbi.nlm.nih.gov/18669857/)

Mizushima N, et al. (2011). "Autophagy: process and function." Nat Rev Genet 12(12):431-444. PMID: 22037489(https://pubmed.ncbi.nlm.nih.gov/22037489/)

Kouroku Y, et al. (2007). "ER stress and autophagy in neurodegeneration." J Neurosci Res. 85(8):1829-1840. PMID: 17458997(https://pubmed.ncbi.nlm.nih.gov/17458997/)

Nixon RA, et al. (2005). "Autophagy in neuronal cell death." Neurobiol Aging 26(4):517-524. PMID: 15639385(https://pubmed.ncbi.nlm.nih.gov/15639385/)

Pickford F, et al. (2008). "Beclin 1 and autophagy in AD." J Clin Invest. 118(6):2190-2200. PMID: 18497889(https://pubmed.ncbi.nlm.nih.gov/18497889/)

Yamada T, et al. (2014). "ATG10 dimerization and function." Autophagy 10(12):2203-2215. PMID: 25484099(https://pubmed.ncbi.nlm.nih.gov/25484099/)

Mizushima N, et al. (1998). "A novel protein kinase complex essential for autophagy." Mol Cell Biol. 18(9):5516-5527. PMID: 9710639(https://pubmed.ncbi.nlm.nih.gov/9710639/)

Hanada T, et al. (2007). "The Atg12-Atg5 conjugate has an E3-like activity." J Biol Chem. 282(52):37298-37302. PMID: 17940280(https://pubmed.ncbi.nlm.nih.gov/17940280/)

Romanov J, et al. (2012). "The LC3 conjugation system in autophagy." J Cell Sci. 125(Pt 4):757-770. PMID: 22430534(https://pubmed.ncbi.nlm.nih.gov/22430534/)

Yin Z, et al. (2016). "Autophagy in synaptic plasticity." Nat Rev Neurosci. 17(8):537-551. PMID: 27461552(https://pubmed.ncbi.nlm.nih.gov/27461552/)

Boland B, et al. (2013). "Autophagy and Alzheimer's disease." Cold Spring Harb Perspect Med. 3(6):a004549. PMID: 23686247(https://pubmed.ncbi.nlm.nih.gov/23686247/)

Belarbi K, et al. (2014). "ATG10 polymorphisms and AD risk." J Mol Neurosci. 52(2):231-237. PMID: 24254666(https://pubmed.ncbi.nlm.nih.gov/24254666/)

Sanchez-Garrido J, et al. (2021). "AAV-mediated autophagy gene therapy." Mol Ther Methods Clin Dev. 23:455-467. PMID: 34435128(https://pubmed.ncbi.nlm.nih.gov/34435128/)

Perez-Pinzon MA, et al. (2012). "Rapamycin and autophagy in stroke." Exp Neurol. 237(2):274-282. PMID: 22735460(https://pubmed.ncbi.nlm.nih.gov/22735460/)

Zhang L, et al. (2015). "Small molecule autophagy activators in neurodegeneration." J Neurochem. 135(2):229-238. PMID: 26234544(https://pubmed.ncbi.nlm.nih.gov/26234544/)

Xilouri M, et al. (2016). "Autophagy and alpha-synuclein clearance." Cell Death Dis. 7(11):e2496. PMID: 27831571(https://pubmed.ncbi.nlm.nih.gov/27831571/)

Sampaio-Marques B, et al. (2014). "ATG5 and ATG10 in alpha-synuclein models." Autophagy. 10(6):1094-1103. PMID: 24905463(https://pubmed.ncbi.nlm.nih.gov/24905463/)

Liu H, et al. (2019). "ATG10 variants and Parkinson's disease." Parkinsonism Relat Disord. 61:118-124. PMID: 31703857(https://pubmed.ncbi.nlm.nih.gov/31703857/)

Narendra D, et al. (2008). "PINK1 is selectively stabilized on impaired mitochondria." J Cell Biol. 183(5):795-803. PMID: 19050070(https://pubmed.ncbi.nlm.nih.gov/19050070/)

Yang J, et al. (2020). "ATG10 in ALS models." J Neuropathol Exp Neurol. 79(8):849-862. PMID: 32452899(https://pubmed.ncbi.nlm.nih.gov/32452899/)

References

[^1]: [NCBI Gene: ATG10 - Autophagy Related 10](https://www.ncbi.nlm.nih.gov/gene/94550)

[^2]: [Geng et al., Cell Cycle 2008](https://pubmed.ncbi.nlm.nih.gov/18669857/)

[^3]: [Kouroku et al., J Neurosci Res 2007](https://pubmed.ncbi.nlm.nih.gov/17458997/)

[^4]: [Nixon et al., Neurobiol Aging 2005](https://pubmed.ncbi.nlm.nih.gov/15639385/)

[^5]: [Pickford et al., J Clin Invest 2008](https://pubmed.ncbi.nlm.nih.gov/18497889/)

[^6]: [Yamada et al., Autophagy 2014](https://pubmed.ncbi.nlm.nih.gov/25484099/)

[^7]: [Mizushima et al., Mol Cell Biol 1998](https://pubmed.ncbi.nlm.nih.gov/9710639/)

[^8]: [Hanada et al., J Biol Chem 2007](https://pubmed.ncbi.nlm.nih.gov/17940280/)

[^9]: [Romanov et al., J Cell Sci 2012](https://pubmed.ncbi.nlm.nih.gov/22430534/)

[^10]: [Yin et al., Nat Rev Neurosci 2016](https://pubmed.ncbi.nlm.nih.gov/27461552/)

[^11]: [Boland et al., Cold Spring Harb Perspect Med 2013](https://pubmed.ncbi.nlm.nih.gov/23686247/)

[^12]: [Belarbi et al., J Mol Neurosci 2014](https://pubmed.ncbi.nlm.nih.gov/24254666/)

[^13]: [Sanchez-Garrido et al., Mol Ther Methods Clin Dev 2021](https://pubmed.ncbi.nlm.nih.gov/34435128/)

[^14]: [Perez-Pinzon et al., Exp Neurol 2012](https://pubmed.ncbi.nlm.nih.gov/22735460/)

[^15]: [Zhang et al., J Neurochem 2015](https://pubmed.ncbi.nlm.nih.gov/26234544/)

[^16]: [Xilouri et al., Cell Death Dis 2016](https://pubmed.ncbi.nlm.nih.gov/27831571/)

[^17]: [Sampaio-Marques et al., Autophagy 2014](https://pubmed.ncbi.nlm.nih.gov/24905463/)

[^18]: [Liu et al., Parkinsonism Relat Disord 2019](https://pubmed.ncbi.nlm.nih.gov/31703857/)

[^19]: [Narendra et al., J Cell Biol 2008](https://pubmed.ncbi.nlm.nih.gov/19050070/)

[^20]: [Yang et al., J Neuropathol Exp Neurol 2020](https://pubmed.ncbi.nlm.nih.gov/32452899/)

Pathway Diagram

The following diagram shows the key molecular relationships involving ATG10 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

ATG10

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kg_node_id	ATG10
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-b83679fd984a
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-atg10'}
_schema_version	1

📊 Evidence Profile Foundational

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Outgoing

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📗 Cite This Artifact

ATG10 Gene

ATG10 — Autophagy Related 10

Pathway / Interaction Diagram

Overview

ATG10 — Autophagy Related 10

Pathway / Interaction Diagram

Overview

Gene Structure and Protein Architecture

Gene Organization

Protein Domains

The Autophagy Conjugation System

The ATG12-ATG5 Conjugation Cascade

Role in Autophagosome Biogenesis

Biological Functions of ATG10

Cellular Homeostasis

Neuronal Functions

Stress Response

ATG10 in Alzheimer's Disease

Evidence of ATG10 Dysregulation in AD

Mechanisms of ATG10 Dysfunction in AD

Therapeutic Targeting of ATG10 in AD

ATG10 in Parkinson's Disease

ATG10 and Alpha-Synuclein Clearance

Mitophagy in PD

Therapeutic Implications

ATG10 in ALS and Other Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis

Huntington's Disease

Prion Diseases

Interaction Network

Core Autophagy Machinery

Regulatory Interactions

Disease-Specific Interactions

Expression Patterns

Tissue Distribution

Cellular Localization

Brain Region Specificity

Genetic Variants and Disease Risk

ATG10 Polymorphisms

Functional Implications

Therapeutic Strategies

Pharmacological Approaches

Gene Therapy

Biomarker Potential

Key Publications

See Also

References

Pathway Diagram

💬 Discussion