ATM Gene

ATM — Ataxia-Telangiectasia Mutated

Pathway Diagram

```mermaid
flowchart TD
ATM["ATM<br/>DNA Damage Response<br/>Kinase"]

DNA_Damage["DNA Double<br/>Strand Breaks"]
DDR["DNA Damage<br/>Response Pathway"]

SQSTM1["SQSTM1/p62<br/>Autophagy Adapter"]
RB1CC1["RB1CC1/FIP200<br/>Autophagy Initiation"]
DNM1L["DNM1L<br/>Mitochondrial Fission"]

BCL2["BCL2<br/>Apoptosis Regulator"]
OPTN["OPTN<br/>Autophagy Receptor"]

Cell_Death["Neuronal<br/>Cell Death"]
Mitochondrial_Dysfunction["Mitochondrial<br/>Dysfunction"]
Autophagy_Defects["Autophagy<br/>Impairment"]

Alzheimer["Alzheimer's<br/>Disease"]
Parkinson["Parkinson's<br/>Disease"]
ALS["Amyotrophic Lateral<br/>Sclerosis"]
MS["Multiple<br/>Sclerosis"]

DNA_Damage -->|"activates"| ATM
ATM -->|"activates"| DDR

ATM -->|"interacts_with"| SQSTM1
ATM -->|"interacts_with"| RB1CC1
ATM -->|"interacts_with"| OPTN
ATM -->|"regulates"| DNM1L
ATM -->|"interacts_with"| BCL2

SQSTM1 -->|"promotes"| Autophagy_Defects
RB1CC1 -->|"impairs"| Autophagy_Defects
DNM1L -->|"causes"| Mitochondrial_Dysfunction
BCL2 -->|"inhibits"| Cell_Death

Autophagy_Defects -->|"contributes_to"| Alzheimer
Mitochondrial_Dysfunction -->|"leads_to"| Parkinson
Cell_Death -->|"causes"| ALS
ATM -->|"associated_with"| MS

style ATM fill:#006494
style DDR fill:#1b5e20
style BCL2 fill:#1b5e20
style SQSTM1 fill:#4a1a6b
style RB1CC1 fill:#4a1a6b
style OPTN fill:#4a1a6b
style DNM1L fill:#4a

ATM — Ataxia-Telangiectasia Mutated

Pathway Diagram

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">ATM</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>ATM</td></tr>
<tr><td><strong>Full Name</strong></td><td>Ataxia-Telangiectasia Mutated</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>11q22.3</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[472](https://www.ncbi.nlm.nih.gov/gene/472)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[607585](https://www.omim.org/entry/607585)</td></tr>
<tr><td><strong>Ensembl</strong></td><td>ENSG00000149311</td></tr>
<tr><td><strong>UniProt</strong></td><td>[Q13315](https://www.uniprot.org/uniprotkb/Q13315)</td></tr>
<tr><td><strong>Major linked conditions</strong></td><td>[Ataxia-Telangiectasia](/diseases/ataxia-telangiectasia), neurodegeneration risk modulation in [Parkinson's disease](/diseases/parkinsons-disease) and [Alzheimer's disease](/diseases/alzheimers)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">861 edges</a></td>
</tr>
</table>
</div>

Overview

ATM is a PIKK-family serine/threonine kinase that coordinates genomic stress responses, especially after DNA double-strand breaks.[@gatti1988][@savitsky1995] In the nervous system, ATM is relevant because [neurons](/entities/neurons) are long-lived, post-mitotic cells that must continuously repair DNA damage without dilution through cell division.[@rothblumoviatt2016][@shiloh2013]

Biallelic pathogenic variants in ATM cause [ataxia-telangiectasia](/diseases/ataxia-telangiectasia), a multisystem disorder with progressive cerebellar neurodegeneration, immunodeficiency, radiosensitivity, and increased cancer risk.[@rothblumoviatt2016][@nahhas2022] Beyond Mendelian disease, ATM signaling intersects with oxidative stress, mitochondrial quality control, and inflammatory pathways that are mechanistically relevant across neurodegenerative disorders.[@shiloh2013][@madabhushi2014]

Core Biology

Protein class and activation

ATM is a large kinase that is normally maintained in an inactive state and becomes activated after DNA double-strand breaks via the MRN complex (MRE11-RAD50-NBS1), followed by phosphorylation cascades involving H2AX, CHK2, p53, BRCA1, and additional repair/checkpoint factors.[@savitsky1995][@bakkenist2003]

Major response outputs include:

• DNA damage checkpoint signaling
• Repair pathway coordination
• Cell-cycle control in dividing cells
• Apoptotic biasing when damage is irreparable

Redox and mitochondrial coupling

ATM also responds to oxidative stress and helps shape antioxidant responses and mitochondrial fitness, including links to mitophagy-related pathways.[@shiloh2013][@valentinvega2012] This is relevant to neurodegeneration because oxidative injury and impaired mitochondrial quality control are shared stressors across [tauopathy](/mechanisms/tauopathy), [synucleinopathy](/mechanisms/alpha-synuclein-aggregation-pathway), and motor neuron disease pathways.[@madabhushi2014][@valentinvega2012]

Nervous System Relevance

Selective neuronal vulnerability

ATM dysfunction does not produce uniform neuronal injury. In ataxia-telangiectasia, cerebellar vulnerability is a defining feature, especially involving Purkinje networks and cerebellar circuit integrity.[@rothblumoviatt2016][@nahhas2022] Proposed contributors include:

• High oxidative load and metabolic demand
• Dependence on precise genome maintenance across lifespan
• Limited regenerative reserve in cerebellar circuitry
• Network-level consequences of persistent DNA damage signaling

Glial and neuroimmune effects

ATM perturbation also affects astrocyte stress responses, including oxidative and endoplasmic-reticulum stress states that can amplify non-cell-autonomous injury to neurons.[@barlow1999] This places ATM at a gene-to-cell-state interface relevant for [neuroinflammation](/mechanisms/neuroinflammation-pathway) and glia-neuron feed-forward loops.

Disease Associations

Ataxia-telangiectasia (high-confidence causal)

This is the best-established ATM neurodegenerative phenotype. Hallmarks include progressive cerebellar ataxia, oculomotor abnormalities, peripheral neuropathy, systemic immune defects, and marked radiosensitivity.[@rothblumoviatt2016][@nahhas2022] The disorder is a direct human model linking deficient DNA-damage signaling to progressive neurodegeneration.

Parkinson's disease (risk/pathway overlap)

ATM is not a major monogenic [Parkinson's](/diseases/parkinsons-disease-disease) gene, but heterozygous variation and pathway-level dysfunction may influence dopaminergic vulnerability in subsets of patients.[@madabhushi2014][@lee2017] Mechanistic overlap is strongest in DNA-repair stress, mitochondrial dysfunction, and oxidative injury convergence rather than a single deterministic ATM-PD axis.[@madabhushi2014][@valentinvega2012]

Alzheimer's disease and related tauopathies (pathway overlap)

AD brains show chronic DNA damage burden and altered stress signaling; ATM pathway dysregulation has been discussed as a contributing modifier of neuronal resilience.[@madabhushi2014][@suberbielle2015] Current evidence supports ATM as a biologically plausible vulnerability node rather than a standalone primary AD driver.

Clinical and Translational Considerations

Biomarker opportunities

Potential translational readouts include:

• Phosphorylated ATM/DDR signatures in blood or CSF-derived compartments
• Multi-marker panels combining DNA damage and neuroaxonal injury markers
• Longitudinal signatures to enrich neuroprotective trials

Therapeutic strategy implications

Given ATM's pleiotropic role, direct inhibition is generally undesirable for neuroprotection. More plausible strategies focus on upstream stress-load reduction and downstream resilience pathways:

• oxidative-stress mitigation
• mitochondrial quality-control support
• precision selection of patients with high DDR burden

Research Priorities

See Also

• [ATM Protein](/proteins/ATM-Protein)
• [DNA Damage Response](/mechanisms/dna-damage-response)
• [Oxidative Stress Pathway](/mechanisms/oxidative-stress-pathway)
• [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction-pathway)
• [Ataxia-Telangiectasia](/diseases/ataxia-telangiectasia)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Alzheimer's Disease](/diseases/alzheimers-disease)

External Links

• [NCBI Gene: ATM (472)](https://www.ncbi.nlm.nih.gov/gene/472)
• [OMIM: ATM](https://www.omim.org/entry/607585)
• [UniProt: ATM (Q13315)](https://www.uniprot.org/uniprotkb/Q13315)

References

Pathway Diagram

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

Expression Profile

Sources: [GTEx Portal v10](https://gtexportal.org/home/gene/atm) | [Allen Brain Atlas](https://www.brain-map.org/)

GTEx Tissue Expression (median TPM)

| Rank | Tissue | Median TPM |
|------|--------|------------|
| 1 | Cells EBV-transformed lymphocytes | 21.03 |
| 2 | Ovary | 18.27 |
| 3 | Spleen | 17.40 |
| 4 | Cells Cultured fibroblasts | 15.77 |
| 5 | Pituitary | 15.34 |
| 6 | Nerve Tibial | 13.72 |
| 7 | Cervix Endocervix | 12.77 |
| 8 | Brain Cerebellum | 12.62 |
| 9 | Uterus | 12.35 |
| 10 | Brain Cerebellar Hemisphere | 12.26 |
| 11 | Cervix Ectocervix | 11.48 |
| 12 | Fallopian Tube | 10.99 |
| 13 | Thyroid | 9.96 |
| 14 | Lung | 9.39 |
| 15 | Small Intestine Terminal Ileum | 9.20 |

Brain-Region Expression:

| Region | Median TPM |
|--------|------------|
| Brain Cerebellum | 12.62 |
| Brain Cerebellar Hemisphere | 12.26 |
| Brain Spinal cord cervical c-1 | 8.22 |