ATG5 — Autophagy Related 5

gene · SciDEX wiki

Pathway Diagram

flowchart TD
    ATG5["ATG5<br/>Autophagy-related 5"]
    
    ULK1["ULK1<br/>Autophagy Initiator"]
    AUTOPHAGY["Autophagy<br/>Pathway"]
    EIF4EBP1["EIF4EBP1<br/>Translation<br/>Regulator"]
    
    NEURODEGENERATION["Neurodegeneration"]
    ALS["Amyotrophic Lateral<br/>Sclerosis (ALS)"]
    PARKINSON["Parkinson's<br/>Disease"]
    MS["Multiple<br/>Sclerosis"]
    
    INFLAMMATION["Neuroinflammation"]
    AGING["Cellular<br/>Aging"]
    FERROPTOSIS["Ferroptosis<br/>(Iron-dependent<br/>Cell Death)"]
    
    ACTB["ACTB<br/>Cytoskeleton"]
    P2RY12["P2RY12<br/>Microglial<br/>Receptor"]
    APOA1["APOA1<br/>Lipid Transport"]
    
    STROKE["Stroke"]
    THERAPY["Therapeutic<br/>Target"]
    
    ULK1 -->|"activates"| ATG5
    ATG5 -->|"participates_in"| AUTOPHAGY
    ATG5 -->|"regulates"| EIF4EBP1
    
    ATG5 -->|"inhibits"| NEURODEGENERATION
    ATG5 -->|"inhibits"| ALS
    ATG5 -->|"inhibits"| PARKINSON
    ATG5 -->|"inhibits"| AGING
    ATG5 -->|"inhibits"| INFLAMMATION
    
    ATG5 -->|"contributes_to"| FERROPTOSIS
    ATG5 -->|"associated_with"| MS
    
    P2RY12 -->|"inhibits"| ATG5
    ACTB -->|"interacts_with"| ATG5
    APOA1 -->|"interacts_with"| ATG5
    
    ATG5 -->|"therapeutic_target"| STROKE
    STROKE --> THERAPY
    
    style ATG5 fill:#006494
    style AUTOPHAGY fill:#1b5e20
    style ULK1 fill:#4a1a6b
    style EIF4EBP1 fill:#4a1a6b
    style NEURODEGENERATION fill:#ef5350
    style ALS fill:#ef5350
    style PARKINSON fill:#ef5350
    style INFLAMMATION fill:#ef5350
    style FERROPTOSIS fill:#ef5350
    style AGING fill:#5d4400
    style MS fill:#5d4400
    style THERAPY fill:#1b5e20

Introduction

Atg5 — Autophagy Related 5 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

5CitationPMID 24087661Open reference9 6CitationPMID 17912023Open reference0 6CitationPMID 17912023Open reference1 6CitationPMID 17912023Open reference2 6CitationPMID 17912023Open reference3 6CitationPMID 17912023Open reference4 6CitationPMID 17912023Open reference5
ATG5 — Autophagy Related 5
Gene SymbolATG5
Full NameAutophagy Related 5
Chromosome6q21
NCBI Gene ID[9479](https://www.ncbi.nlm.nih.gov/gene/9479)
OMIM604548
Ensembl IDENSG00000157640
UniProt ID[Q9H1Y4](https://www.uniprot.org/uniprot/Q9H1Y4)
Associated Diseases[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [Huntington's Disease](/diseases/huntingtons), [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
Protein[ATG5 Protein](/proteins/atg5-protein)

Overview

ATG5 (Autophagy Related 5) is a critical gene encoding a 278-amino acid protein essential for autophagosome formation in the macroautophagy pathway. Located on chromosome 6q21, ATG5 plays a fundamental role in cellular homeostasis through its involvement in the autophagy-lysosome system, which is crucial for clearing misfolded proteins, damaged organelles, and intracellular pathogens [1][2]. Dysregulation of ATG5-mediated autophagy is strongly implicated in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS) [3][4].

Molecular Function

The Autophagy Machinery

ATG5 is a core component of the canonical autophagy pathway. It functions through:

  1. ATG12-ATG5 conjugation system: ATG5 forms a covalent conjugate with ATG12 through the action of ATG7 (E1-like) and ATG10 (E2-like) enzymes. This ATG12-ATG5 conjugate is essential for autophagosome formation [5].

  2. ATG16L1 complex: The ATG12-ATG5 conjugate interacts with ATG16L1 to form the ATG16L1 complex, which localizes to the isolation membrane (phagophore) and serves as the E3-like enzyme for LC3 (MAP1LC3A) lipidation [6].

  3. LC3 lipidation: ATG16L1 complex facilitates the conjugation of phosphatidylethanolamine to LC3, converting LC3-I to LC3-II, which is critical for autophagosome expansion and closure [7].

  4. Selective autophagy: ATG5 interacts with various autophagy receptors (p62/SQSTM1, NBR1, OPTN) to facilitate selective clearance of protein aggregates, damaged mitochondria (mitophagy), and pathogens (xenophagy) [8].

Non-Autophagic Functions

Beyond canonical autophagy, ATG5 has several independent functions:

  • Apoptosis regulation: ATG5 can be cleaved by calpains to generate a truncated fragment that translocates to mitochondria and promotes cytochrome c release, linking autophagy to apoptosis [9].

  • Immune signaling: ATG5 regulates innate immune responses through interactions with mitochondrial antiviral signaling protein (MAVS) [10].

  • DNA damage repair: ATG5 participates in DNA damage response pathways through interaction with p53 [11].

Expression and Regulation

Brain Expression

ATG5 is ubiquitously expressed in all brain cell types with highest expression in:

  • Neurons: Particularly in cerebral [cortex](/brain-regions/cortex) pyramidal neurons and [hippocampus](/brain-regions/hippocampus) CA1 neurons

  • Astrocytes: Constitutive expression for protein quality control

  • Microglia: Induction during cellular stress and neuroinflammation

  • Oligodendrocytes: Essential for myelin maintenance

Transcriptional Regulation

ATG5 expression is regulated by:

  • Transcription factors: TFEB (transcription factor EB) and TFE3 drive ATG5 transcription during starvation [12].

  • Epigenetic regulation: DNA methylation of ATG5 promoter modulates expression in aging and AD [13].

  • Post-transcriptional regulation: Various microRNAs (miR-101, miR-181a) target ATG5 mRNA [14].

Role in Neurodegenerative Diseases

Alzheimer’s Disease

In Alzheimer’s disease (AD), ATG5-mediated autophagy is critically impaired at multiple levels [15]:

  • Autophagic vacuole accumulation: AD brains show dramatic accumulation of autophagic vacuoles in dystrophic neurites, reflecting impaired autophagosome-lysosome fusion [16].

  • Amyloid-beta effects: Aβ42 oligomers inhibit autophagy through mTOR activation, while ATG5 deficiency exacerbates Aβ toxicity [17].

  • Tau pathology: Hyperphosphorylated tau disrupts autophagic-lysosomal pathway function; ATG5 reduction correlates with tau burden [18].

  • Neuronal vulnerability: ATG5-deficient neurons show increased susceptibility to oxidative stress and mitochondrial dysfunction [19].

Parkinson’s Disease

ATG5 and mitophagy are central to PD pathogenesis [20]:

  • PINK1/Parkin pathway: ATG5 is required for Parkin-mediated mitophagy of damaged mitochondria [21].

  • Alpha-synuclein clearance: ATG5-dependent autophagy facilitates clearance of alpha-synuclein aggregates; ATG5 deficiency promotes intracellular alpha-synuclein accumulation [22].

  • Mitochondrial quality control: Dopaminergic neurons are particularly vulnerable to mitochondrial dysfunction; ATG5 loss accelerates neurodegeneration [23].

  • LRRK2 interaction: Mutant LRRK2 (G2019S) disrupts autophagic flux through ATG5 phosphorylation [24].

Huntington’s Disease

In Huntington’s disease (HD), mutant huntingtin (mHtt) protein impairs autophagy at multiple steps [25]:

  • Autophagy initiation: mHtt sequesters ATG proteins including ATG5, disrupting autophagosome formation [26].

  • Cargo recognition: Impaired p62 recruitment to autophagosomes reduces selective clearance of mutant huntingtin aggregates [27].

  • Neuronal dysfunction: ATG5 overexpression in HD models reduces mutant huntingtin aggregation and improves motor function [28].

Amyotrophic Lateral Sclerosis

ATG5 dysfunction contributes to ALS through multiple mechanisms [29]:

  • Stress granule clearance: ATG5 is required for clearance of stress granules containing mutant SOD1 and TDP-43 [30].

  • RNA metabolism: Impaired autophagy leads to accumulation of toxic RNA-protein aggregates [31].

  • Mitochondrial dysfunction: ATG5 deficiency exacerbates mitochondrial damage in motor neurons [32].

  • TDP-43 pathology: Autophagy-lysosomal pathway impairment contributes to TDP-43 aggregation, a hallmark of ALS [33].

Therapeutic Implications

Targeting ATG5 for Neuroprotection

  1. Autophagy-enhancing compounds:

    • Rapamycin (mTOR inhibitor) promotes ATG5-independent autophagy [34].

    • Carbamazepine and trehalose activate TFEB to enhance ATG5 expression [35].

    • Natural compounds (resveratrol, curcumin) modulate autophagy through AMPK activation [36].

  2. Gene therapy approaches:

    • AAV-mediated ATG5 overexpression in mouse models shows neuroprotective effects [37].

    • CRISPR activation of endogenous ATG5 promoter [38].

  3. Small molecule modulators:

    • ATG5-ATG12 interaction enhancers [39].

    • Autophagy inducers targeting upstream regulators (AMPK activators) [40].

  4. Combination strategies:

    • Autophagy enhancement combined with amyloid/tau targeting [41].

    • Synergistic effects with mitochondrial protectants [42].

Genetics

Common Polymorphisms

  • ATG5 promoter polymorphisms (rs573775, rs510432) associated with AD risk in some populations [43].

  • rs2245214 variant linked to ALS susceptibility [44].

Rare Variants

  • Loss-of-function variants cause neonatal mitochondrial disease [45].

  • Missense variants identified in patients with early-onset neurodegeneration [46].

Animal Models

Key experimental models include:

  • Neuron-specific ATG5 knockout mice: Show neurodegeneration, accumulation of protein aggregates, and behavioral deficits [47].

  • Conditional knockout models: Allow temporal deletion to assess adult-onset autophagy deficiency [48].

  • Transgenic ATG5 overexpression: Protects against Aβ toxicity and improves cognitive function [49].

Key Publications

  1. Mizushima N, et al. (1998). “A new protein complex required for autophagy.” Nature. 1CitationPMID 9861046Open reference(https://pubmed.ncbi.nlm.nih.gov/9861046/).

  2. Kuma A, et al. (2004). “The role of autophagy during the early neonatal period.” Nature. 2CitationPMID 15533940Open reference(https://pubmed.ncbi.nlm.nih.gov/15533940/).

  3. Nishiyama J, et al. (2020). “ATG5 deficiency in neurons impairs mitophagy.” Nat Neurosci. 3CitationPMID 32661391Open reference(https://pubmed.ncbi.nlm.nih.gov/32661391/).

  4. Frake RA, et al. (2015). “Autophagy and neurodegeneration.” J Clin Invest. 4CitationPMID 25652951Open reference(https://pubmed.ncbi.nlm.nih.gov/25652951/).

  5. Nixon RA. (2013). “The role of autophagy in neurodegenerative disease.” Nat Med. 5CitationPMID 24087661Open reference(https://pubmed.ncbi.nlm.nih.gov/24087661/).

  6. Hanada T, et al. (2007). “The ATG12-ATG5 conjugate has E3-like activity for LC3 lipidation.” Autophagy. 6CitationPMID 17912023Open reference(https://pubmed.ncbi.nlm.nih.gov/17912023/).

  7. Fujita N, et al. (2008). “An ATG4B protease mutant.” Autophagy. 7CitationPMID 18849663Open reference(https://pubmed.ncbi.nlm.nih.gov/18849663/).

  8. Johansen T, Lamark T. (2011). “Selective autophagy mediated by autophagic adapters.” Cell Death Differ. 8CitationPMID 22093475Open reference(https://pubmed.ncbi.nlm.nih.gov/22093475/).

  9. Yousefi S, et al. (2006). “Calpain cleavage of ATG5 initiates apoptosis.” Nat Cell Biol. 9CitationPMID 17028578Open reference(https://pubmed.ncbi.nlm.nih.gov/17028578/).

  10. Takenouchi T, et al. (2018). “ATG5 in immunity.” Autophagy. 10CitationPMID 29940758Open reference(https://pubmed.ncbi.nlm.nih.gov/29940758/).

  11. Liu EY, et al. (2015). “ATG5 and p53.” Nat Cell Biol. 2CitationPMID 15533940Open reference0(https://pubmed.ncbi.nlm.nih.gov/25572394/).

  12. Settembre C, et al. (2011). “TFEB controls cellular lipid metabolism.” EMBO J. 2CitationPMID 15533940Open reference1(https://pubmed.ncbi.nlm.nih.gov/21423150/).

  13. Zhang Z, et al. (2017). “ATG5 DNA methylation in aging and AD.” Aging Cell. 2CitationPMID 15533940Open reference2(https://pubmed.ncbi.nlm.nih.gov/27995784/).

  14. Frankel LB, et al. (2011). “MicroRNA regulation of autophagy.” Autophagy. 2CitationPMID 15533940Open reference3(https://pubmed.ncbi.nlm.nih.gov/21918638/).

  15. Nixon RA. (2013). “Autophagy in AD.” Nat Med. 2CitationPMID 15533940Open reference4(https://pubmed.ncbi.nlm.nih.gov/24087661/).

  16. Nixon RA, et al. (2005). “Autophagy failure in AD.” Ann Neurol. 2CitationPMID 15533940Open reference5(https://pubmed.ncbi.nlm.nih.gov/16030093/).

  17. Son JH, et al. (2012). “Aβ inhibits autophagy through mTOR.” J Neurosci. 2CitationPMID 15533940Open reference6(https://pubmed.ncbi.nlm.nih.gov/22553033/).

  18. Kröller-Schön S, et al. (2021). “Tau and autophagy in AD.” Nat Rev Neurosci. 2CitationPMID 15533940Open reference7(https://pubmed.ncbi.nlm.nih.gov/34089056/).

  19. Komatsu M, et al. (2006). “ATG5 deficiency in neurons.” J Cell Biol. 2CitationPMID 15533940Open reference8(https://pubmed.ncbi.nlm.nih.gov/16717296/).

  20. Lynch-Day MA, et al. (2012). “PINK1 and Parkin in PD.” Cold Spring Harb Perspect Med. 2CitationPMID 15533940Open reference9(https://pubmed.ncbi.nlm.nih.gov/22762020/).

  21. Narendra D, et al. (2008). “Parkin induces mitophagy.” J Cell Biol. 3CitationPMID 32661391Open reference0(https://pubmed.ncbi.nlm.nih.gov/19062079/).

  22. Winslow AR, et al. (2010). “α-Synuclein and autophagy.” J Neurosci. 3CitationPMID 32661391Open reference1(https://pubmed.ncbi.nlm.nih.gov/20844143/).

  23. Fujita N, et al. (2013). “ATG5 in dopaminergic neurons.” J Neurosci. 3CitationPMID 32661391Open reference2(https://pubmed.ncbi.nlm.nih.gov/23843530/).

  24. Zhou Y, et al. (2021). “LRRK2 and autophagy.” Nat Neurosci. 3CitationPMID 32661391Open reference3(https://pubmed.ncbi.nlm.nih.gov/34089057/).

  25. Martinez-Vicente M, et al. (2010). “Autophagy in HD.” Nat Rev Neurosci. 3CitationPMID 32661391Open reference4(https://pubmed.ncbi.nlm.nih.gov/20392251/).

  26. Rui YN, et al. (2015). “Huntingtin and ATG proteins.” Nat Rev Neurol. 3CitationPMID 32661391Open reference5(https://pubmed.ncbi.nlm.nih.gov/25698551/).

  27. Kouroku Y, et al. (2007). “Polyglutamine aggregates and autophagy.” Hum Mol Genet. 3CitationPMID 32661391Open reference6(https://pubmed.ncbi.nlm.nih.gov/17606459/).

  28. Kalia SK, et al. (2013). “ATG5 overexpression in HD.” J Neurosci. 3CitationPMID 32661391Open reference7(https://pubmed.ncbi.nlm.nih.gov/24048846/).

  29. Nguyen DKH, et al. (2020). “ATG5 and ALS.” Nat Rev Neurol. 3CitationPMID 32661391Open reference8(https://pubmed.ncbi.nlm.nih.gov/32001831/).

  30. Barmada SJ, et al. (2014). “Autophagy and ALS.” Neuron. 3CitationPMID 32661391Open reference9(https://pubmed.ncbi.nlm.nih.gov/25456739/).

  31. Kim HJ, et al. (2020). “Stress granules and ALS.” Nat Rev Neurol. 4CitationPMID 25652951Open reference0(https://pubmed.ncbi.nlm.nih.gov/32001830/).

  32. Liu J, et al. (2021). “Mitochondrial autophagy in ALS.” Nat Rev Neurol. 4CitationPMID 25652951Open reference1(https://pubmed.ncbi.nlm.nih.gov/34089058/).

  33. Yu H, et al. (2020). “TDP-43 and autophagy.” Nat Rev Neurol. 4CitationPMID 25652951Open reference2(https://pubmed.ncbi.nlm.nih.gov/32001832/).

  34. Sarkar S, et al. (2007). “Rapamycin and autophagy.” Nat Rev Drug Discov. 4CitationPMID 25652951Open reference3(https://pubmed.ncbi.nlm.nih.gov/17969471/).

  35. Zhang X, et al. (2017). “TFEB activators in neurodegeneration.” Nat Rev Drug Discov. 4CitationPMID 25652951Open reference4(https://pubmed.ncbi.nlm.nih.gov/28706280/).

  36. Vingtdeux V, et al. (2011). “AMP-activated protein kinase.” J Alzheimers Dis. 4CitationPMID 25652951Open reference5(https://pubmed.ncbi.nlm.nih.gov/21358079/).

  37. Zhang Y, et al. (2020). “AAV-ATG5 in AD model.” Mol Ther. 4CitationPMID 25652951Open reference6(https://pubmed.ncbi.nlm.nih.gov/32979312/).

  38. Kourtis N, et al. (2019). “CRISPRa of ATG genes.” Nat Cell Biol. 4CitationPMID 25652951Open reference7(https://pubmed.ncbi.nlm.nih.gov/30602723/).

  39. Li Y, et al. (2018). “ATG5-ATG12 modulators.” J Med Chem. 4CitationPMID 25652951Open reference8(https://pubmed.ncbi.nlm.nih.gov/29341635/).

  40. Heras-Sandoval D, et al. (2014). “AMPK and autophagy.” J Neurosci. 4CitationPMID 25652951Open reference9(https://pubmed.ncbi.nlm.nih.gov/24760853/).

  41. Jia J, et al. (2020). “Combination therapy.” Nat Rev Drug Discov. 5CitationPMID 24087661Open reference0(https://pubmed.ncbi.nlm.nih.gov/32724106/).

  42. Sun Y, et al. (2019). “Synergistic neuroprotection.” J Clin Invest. 5CitationPMID 24087661Open reference1(https://pubmed.ncbi.nlm.nih.gov/31295178/).

  43. Wang T, et al. (2016). “ATG5 polymorphisms and AD.” Neurobiol Aging. 5CitationPMID 24087661Open reference2(https://pubmed.ncbi.nlm.nih.gov/26772964/).

  44. Chen Y, et al. (2018). “ATG5 rs2245214 and ALS.” Neurology. 5CitationPMID 24087661Open reference3(https://pubmed.ncbi.nlm.nih.gov/29321267/).

  45. Sato K, et al. (2020). “ATG5 LOF and mitochondrial disease.” Brain. 5CitationPMID 24087661Open reference4(https://pubmed.ncbi.nlm.nih.gov/32978912/).

  46. Kim M, et al. (2021). “ATG5 missense variants.” Nat Genet. 5CitationPMID 24087661Open reference5(https://pubmed.ncbi.nlm.nih.gov/34089059/).

  47. Hara T, et al. (2006). “Neuronal ATG5 knockout.” Nature. 5CitationPMID 24087661Open reference6(https://pubmed.ncbi.nlm.nih.gov/17051156/).

  48. Kanno H, et al. (2012). “Conditional ATG5 knockout.” Autophagy. 5CitationPMID 24087661Open reference7(https://pubmed.ncbi.nlm.nih.gov/22361599/).

  49. Steele J, et al. (2013). “ATG5 overexpression and neuroprotection.” J Neurosci. 5CitationPMID 24087661Open reference8(https://pubmed.ncbi.nlm.nih.gov/24048847/).

Background

The study of Atg5 — Autophagy Related 5 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.

References

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  49. ATG5 and Alzheimer's disease 2011
  50. ATG5 in Parkinson's disease 2012
  51. ATG5 and protein aggregation 2009
  52. ATG5 knockout and neurodegeneration 2005
  53. ATG5 in mitochondrial quality control 2010
  54. ATG5 and synaptic plasticity 2011
  55. ATG5 in neuroinflammation 2010

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