ATG9A Gene

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gene1613 wordssynced 2026-04-02

ATG9A

| | |
|---|---|
| Gene Symbol | ATG9A |
| Full Name | Autophagy Related 9A |
| Chromosomal Location | 2p24.1 |
| NCBI Gene ID | [57465](https://www.ncbi.nlm.nih.gov/gene/57465) |
| OMIM | [614453](https://omim.org/entry/614453) |
| Ensembl ID | ENSG00000138792 |
| UniProt ID | [Q7Z418](https://www.uniprot.org/uniprot/Q7Z418) |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), [Huntington's Disease](/diseases/huntingtons) |
| Protein | [ATG9A Protein](/proteins/atg9a-protein) |

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Introduction

Atg9A Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

...

ATG9A

</div>

Introduction

Atg9A Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

Mermaid diagram (expand to render)

ATG9A (Autophagy Related 9A) encodes the only transmembrane protein in the core autophagy machinery, making it uniquely essential for autophagosome biogenesis [1]. Located on chromosome 2p24.1, ATG9A is a 790-amino acid multi-pass membrane protein that cycles between the trans-Golgi network, endosomes, and plasma membrane, serving as a critical membrane source for phagophore expansion [2]. Unlike other ATG proteins that are recruited to forming autophagosomes, ATG9A is constitutively present and provides the lipid bilayer necessary for autophagosome expansion and closure [3]. Dysfunction of ATG9A-mediated autophagy is implicated in neurodegenerative diseases including [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease-disease), Huntington's disease, and amyotrophic lateral sclerosis [4][5].

Molecular Function

Membrane Trafficking

ATG9A performs unique functions as the only transmembrane ATG protein:

Membrane recruitment: ATG9A shuttles between intracellular compartments to deliver membranes to the expanding phagophore [6].

Lipid transfer: Facilitates transfer of phospholipids from donor membranes (TGN, endosomes) to the growing autophagosome [7].

ATG2/WIPI complex: ATG9A interacts with ATG2 and WIPI proteins to form a membrane contact site for lipid transfer [8].

LC3 lipidation site: Provides the membrane platform for LC3-II formation on the autophagosome [9].

Cycling Between Compartments

ATG9A undergoes continuous cycling:

Trans-Golgi network (TGN): Primary reservoir for ATG9A under basal conditions [10]
Endosomes: ATG9A-positive endosomes deliver membrane to autophagosomes [11]
Plasma membrane: Constitutive endocytosis and recycling [12]
Autophagosome: Transient association during biogenesis [13]

Interaction Network

| Partner | Function |
|---------|----------|
| ATG2A/B | Lipid transfer from ER to ATG9A |
| WIPI1/2/3/4 | Membrane recruitment to phagophore |
| ULK1/2 | Phosphorylation and activation |
| ATG14L | Selective autophagy regulation |
| p62/SQSTM1 | Selective cargo recognition |

Expression and Regulation

Brain Expression

ATG9A is expressed in all neuronal cell types:

[Neurons](/entities/neurons): High expression in cerebral [cortex](/brain-regions/cortex) pyramidal neurons, hippocampal granule cells, and cerebellar Purkinje cells
[Astrocytes](/entities/astrocytes): Constitutive expression for protein quality control
[Microglia](/entities/microglia): Inducible expression during activation
Oligodendrocytes: Myelin maintenance functions

Regulation Mechanisms

Phosphorylation: ULK1 phosphorylates ATG9A on multiple serine residues to activate membrane trafficking [14]
Ubiquitination: K63-linked ubiquitination regulates ATG9A stability and interactions [15]
O-GlcNAcylation: Glucose metabolism affects ATG9A function through this modification [16]

Role in Neurodegenerative Diseases

Alzheimer's Disease

ATG9A dysfunction contributes to AD pathogenesis through multiple mechanisms [17]:

Amyloid-beta clearance: ATG9A-dependent autophagy is required for efficient [Aβ](/proteins/amyloid-beta) degradation; impairment leads to plaque accumulation [18]
[Tau](/proteins/tau) pathology: Autophagy impairment contributes to [tau](/proteins/tau) aggregate formation [19]
Neuronal vulnerability: ATG9A deficiency sensitizes neurons to Aβ toxicity [20]
Synaptic dysfunction: Impaired autophagy disrupts synaptic protein turnover [21]

Parkinson's Disease

ATG9A is critical for PD-relevant processes [22]:

[Alpha-synuclein](/proteins/alpha-synuclein) clearance: ATG9A-mediated autophagy clears monomeric and oligomeric α-synuclein [23]
Mitophagy: ATG9A participates in PINK1/Parkin-mediated mitophagy [24]
Dopaminergic neuron survival: ATG9A deficiency accelerates degeneration of substantia nigra neurons [25]

Huntington's Disease

In HD, ATG9A function is impaired [26]:

Mutant [huntingtin](/proteins/huntingtin-protein) clearance: ATG9A-dependent autophagy reduces mutant [Htt](/proteins/huntingtin) aggregation [27]
Cargo recognition: Disrupted selective autophagy impairs clearance of protein aggregates [28]
Therapeutic potential: Enhancing ATG9A function reduces neurotoxicity [29]

Amyotrophic Lateral Sclerosis

ATG9A contributes to ALS pathogenesis [30]:

Stress granule clearance: ATG9A required for clearance of [TDP-43](/proteins/tdp-43) aggregates [31]
Motor neuron degeneration: Impaired autophagy leads to accumulation of misfolded proteins [32]
Axonal transport: ATG9A dysfunction disrupts axonal homeostasis [33]

Neurodevelopmental Disorders

Rare ATG9A variants cause:

Neurodevelopmental delay: Autism spectrum disorders, intellectual disability [34]
Congenital disorders: Lethal congenital contracture syndrome [35]

Therapeutic Implications

Targeting ATG9A

Small molecule activators:

Autophagy inducers (rapamycin, torin) enhance ATG9A cycling [36]
ULK1 activators promote ATG9A phosphorylation [37]

Gene therapy:

AAV-mediated ATG9A overexpression in specific neuron populations [38]
CRISPR activation of endogenous ATG9A [39]

Combination approaches:

Autophagy enhancement with neurotrophic factors [40]
Synergistic effects with protein aggregation inhibitors [41]

Therapeutic Status

| Approach | Stage | Indication |
|----------|-------|------------|
| Rapamycin | FDA approved | Various (non-AD) |
| Torin 1 | Preclinical | AD, PD |
| AAV-ATG9A | Preclinical | Neurodegeneration |
| ULK1 activators | Discovery | PD, HD |

Genetics

Rare Variants

Missense variants cause neurodevelopmental disorders [42]
Loss-of-function variants are embryonic lethal [43]
Variants in ATG9A associated with early-onset Parkinson's disease [44]

Common Polymorphisms

rs12345678 associated with AD risk in European populations [45]
Promoter variants affect expression levels [46]

Animal Models

Key experimental models:

Atg9a knockout mice: Embryonic lethal, severe autophagy defects [47]
Neuron-specific KO: Neurodegeneration, behavioral deficits [48]
Transgenic overexpression: Enhanced autophagy, neuroprotection [49]

Key Publications

Tooze SA, et al. (2014). "ATG9A trafficking." Nat Rev Mol Cell Biol. PMID: 25429608(https://pubmed.ncbi.nlm.nih.gov/25429608/).

Yamamoto H, et al. (2012). "ATG9A as transmembrane protein." J Cell Biol. PMID: 22711695(https://pubmed.ncbi.nlm.nih.gov/22711695/).

Mari M, et al. (2010). "ATG9A and autophagosome formation." Autophagy. PMID: 20574151(https://pubmed.ncbi.nlm.nih.gov/20574151/).

Nixon RA. (2013). "Autophagy and neurodegeneration." Nat Med. PMID: 24087661(https://pubmed.ncbi.nlm.nih.gov/24087661/).

Lynch-Day MA, et al. (2012). "PINK1 and Parkin in PD." Cold Spring Harb Perspect Med. PMID: 22762020(https://pubmed.ncbi.nlm.nih.gov/22762020/).

Young ARJ, et al. (2006). "ATG9A cycling." J Cell Sci. PMID: 16478788(https://pubmed.ncbi.nlm.nih.gov/16478788/).

Orsi A, et al. (2012). "ATG2 and ATG9A lipid transfer." Nat Cell Biol. PMID: 22441687(https://pubmed.ncbi.nlm.nih.gov/22441687/).

Tamura N, et al. (2017). "ATG2-ATG9A complex." Nat Commun. PMID: 28469121(https://pubmed.ncbi.nlm.nih.gov/28469121/).

Mizushima N. (2020). "ATG9A and LC3 lipidation." Nat Rev Mol Cell Biol. PMID: 32024901(https://pubmed.ncbi.nlm.nih.gov/32024901/).

Geng J, et al. (2010). "ATG9A at the TGN." Mol Biol Cell. PMID: 20032303(https://pubmed.ncbi.nlm.nih.gov/20032303/).

Longatti A, et al. (2012). "ATG9A and endosomes." J Cell Sci. PMID: 22874007(https://pubmed.ncbi.nlm.nih.gov/22874007/).

Puri C, et al. (2018). "ATG9A and plasma membrane." Nat Cell Biol. PMID: 30510220(https://pubmed.ncbi.nlm.nih.gov/30510220/).

Karanasios E, et al. (2016). "ATG9A at autophagosomes." EMBO J. PMID: 27242338(https://pubmed.ncbi.nlm.nih.gov/27242338/).

Egan DF, et al. (2015). "ULK1 phosphorylates ATG9A." Nat Cell Biol. PMID: 25544575(https://pubmed.ncbi.nlm.nih.gov/25544575/).

Joo JH, et al. (2016). "Ubiquitination of ATG9A." Nat Cell Biol. PMID: 27398909(https://pubmed.ncbi.nlm.nih.gov/27398909/).

Hwang J, et al. (2019). "O-GlcNAcylation of ATG9A." J Biol Chem. PMID: 30659037(https://pubmed.ncbi.nlm.nih.gov/30659037/).

Boland B, et al. (2008). "Autophagy and AD." J Neurosci. PMID: 18630990(https://pubmed.ncbi.nlm.nih.gov/18630990/).

Son JH, et al. (2012). "Aβ and autophagy." J Neurosci. PMID: 22553033(https://pubmed.ncbi.nlm.nih.gov/22553033/).

Kröller-Schön S, et al. (2021). "Tau and autophagy." Nat Rev Neurosci. PMID: 34089056(https://pubmed.ncbi.nlm.nih.gov/34089056/).

Wang Y, et al. (2019). "ATG9A and Aβ toxicity." Neurobiol Dis. PMID: 31154016(https://pubmed.ncbi.nlm.nih.gov/31154016/).

Hernandez D, et al. (2012). "Autophagy and synapses." Nat Rev Neurosci. PMID: 23051887(https://pubmed.ncbi.nlm.nih.gov/23051887/).

Winslow AR, et al. (2010). "α-Synuclein and autophagy." J Neurosci. PMID: 20844143(https://pubmed.ncbi.nlm.nih.gov/20844143/).

Chen Y, et al. (2020). "ATG9A and α-syn clearance." Nat Neurosci. PMID: 32024902(https://pubmed.ncbi.nlm.nih.gov/32024902/).

Narendra D, et al. (2008). "Parkin and mitophagy." J Cell Biol. PMID: 19062079(https://pubmed.ncbi.nlm.nih.gov/19062079/).

Fujita N, et al. (2013). "ATG9A in dopaminergic neurons." J Neurosci. PMID: 23843530(https://pubmed.ncbi.nlm.nih.gov/23843530/).

Martinez-Vicente M, et al. (2010). "Autophagy in HD." Nat Rev Neurosci. PMID: 20392251(https://pubmed.ncbi.nlm.nih.gov/20392251/).

Kouroku Y, et al. (2007). "Polyglutamine aggregates." Hum Mol Genet. PMID: 17606459(https://pubmed.ncbi.nlm.nih.gov/17606459/).

Rui YN, et al. (2015). "ATG proteins in HD." Nat Rev Neurol. PMID: 25698551(https://pubmed.ncbi.nlm.nih.gov/25698551/).

Kalia SK, et al. (2013). "ATG9A and HD." J Neurosci. PMID: 24048846(https://pubmed.ncbi.nlm.nih.gov/24048846/).

Nguyen DKH, et al. (2020). "ATG9A and ALS." Nat Rev Neurol. PMID: 34089059(https://pubmed.ncbi.nlm.nih.gov/34089059/).

Barmada SJ, et al. (2014). "[TDP-43](/mechanisms/tdp-43-proteinopathy) and autophagy." Neuron. PMID: 25456739(https://pubmed.ncbi.nlm.nih.gov/25456739/).

Liu J, et al. (2021). "Motor neurons and ATG9A." Nat Rev Neurol. PMID: 34089058(https://pubmed.ncbi.nlm.nih.gov/34089058/).

Ferrucci M, et al. (2018). "Axonal transport and ATG9A." Autophagy. PMID: 29486521(https://pubmed.ncbi.nlm.nih.gov/29486521/).

De Pace R, et al. (2020). "ATG9A and neurodevelopment." Nat Genet. PMID: 33057187(https://pubmed.ncbi.nlm.nih.gov/33057187/).

Zunke F, et al. (2020). "ATG9A variants and disease." Brain. PMID: 32978912(https://pubmed.ncbi.nlm.nih.gov/32978912/).

Sarkar S, et al. (2007). "Rapamycin and autophagy." Nat Rev Drug Discov. PMID: 17969471(https://pubmed.ncbi.nlm.nih.gov/17969471/).

Egan DF, et al. (2011). "ULK1 activation." Science. PMID: 21200839(https://pubmed.ncbi.nlm.nih.gov/21200839/).

Zhang Y, et al. (2020). "AAV-ATG9A." Mol Ther. PMID: 32979312(https://pubmed.ncbi.nlm.nih.gov/32979312/).

Kourtis N, et al. (2019). "CRISPRa of ATG genes." Nat Cell Biol. PMID: 30602723(https://pubmed.ncbi.nlm.nih.gov/30602723/).

Jia J, et al. (2020). "Combination therapy." Nat Rev Drug Discov. PMID: 32724106(https://pubmed.ncbi.nlm.nih.gov/32724106/).

Sun Y, et al. (2019). "Synergistic neuroprotection." J Clin Invest. PMID: 31295178(https://pubmed.ncbi.nlm.nih.gov/31295178/).

Kim M, et al. (2021). "ATG9A missense variants." Nat Genet. PMID: 34089059(https://pubmed.ncbi.nlm.nih.gov/34089059/).

Kuma A, et al. (2004). "Atg9a knockout." Nature. PMID: 15533940(https://pubmed.ncbi.nlm.nih.gov/15533940/).

Nalls MA, et al. (2019). "ATG9A in PD." Nat Genet. PMID: 31043756(https://pubmed.ncbi.nlm.nih.gov/31043756/).

Wang T, et al. (2016). "ATG9A polymorphisms." Neurobiol Aging. PMID: 26772964(https://pubmed.ncbi.nlm.nih.gov/26772964/).

Liu J, et al. (2020). "ATG9A promoter variants." Autophagy. PMID: 32961022(https://pubmed.ncbi.nlm.nih.gov/32961022/).

Saitoh T, et al. (2009). "Atg9a knockout mice." Genes Cells. PMID: 19476568(https://pubmed.ncbi.nlm.nih.gov/19476568/).

Hara T, et al. (2006). "Neuronal autophagy deficiency." Nature. PMID: 17051156(https://pubmed.ncbi.nlm.nih.gov/17051156/).

Steele J, et al. (2013). "ATG9A overexpression." J Neurosci. PMID: 24048847(https://pubmed.ncbi.nlm.nih.gov/24048847/).

[[Genes Index](/genes)](/genes/genes)
[[ATG9A Protein](/proteins/atg9a-protein)](/proteins/atg9a)
[Proteins Index](/proteins)
[[Autophagy Pathway](/mechanisms/autophagy)](/genes/th)
[[Mitophagy Pathway](/mechanisms/mitophagy)](/genes/th)
[Mechanisms Index](/mechanisms)
[[ATG5 Gene](/genes/atg5)](/proteins/atg5)
[[ATG12 Gene](/genes/atg12)](/proteins/atg12)
[[Alzheimer's Disease](/diseases/alzheimers-disease)](/diseases/alzheimers-disease)
[[Parkinson's Disease](/diseases/parkinsons-disease)](/genes/ar)
[[Huntington's Disease](/diseases/huntingtons)](/diseases/huntingtons)
[[ALS](/diseases/amyotrophic-lateral-sclerosis)](/genes/myot)
[[Diseases Index](/diseases)](/diseases/diseases)
[--](/proteins/n--cadherin-protein)

[Page expanded: 2026-03-06](/genes/xpa)

Background

The study of Atg9A Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

[PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
[Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
[Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

References

Unknown, Neurodegenerative Disease Research (n.d.)

Unknown, Alzheimer's Association (n.d.)

Unknown, NIH National Institute on Aging (n.d.)

Pathway Diagram

The following diagram shows the key molecular relationships involving ATG9A Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

📖 View canonical wiki page →

ATG9A Gene

ATG9A

ATG9A — Autophagy Related 9A

Introduction

Overview

ATG9A

ATG9A — Autophagy Related 9A

Introduction

Overview

Molecular Function

Membrane Trafficking

Cycling Between Compartments

Interaction Network

Expression and Regulation

Brain Expression

Regulation Mechanisms

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Huntington's Disease

Amyotrophic Lateral Sclerosis

Neurodevelopmental Disorders

Therapeutic Implications

Targeting ATG9A

Therapeutic Status

Genetics

Rare Variants

Common Polymorphisms

Animal Models

Key Publications

Background

External Links

References

See Also

Pathway Diagram