| ATM | |
|---|---|
| Gene Symbol | ATM |
| Full Name | Ataxia-Telangiectasia Mutated |
| Chromosomal Location | 11q22.3 |
| NCBI Gene ID | 472 |
| OMIM | 607585 |
| Ensembl | ENSG00000149311 |
| UniProt | Q13315 |
| Major linked conditions | Ataxia-Telangiectasia, neurodegeneration risk modulation in Parkinson's disease and Alzheimer's disease |
ATM is a PIKK-family serine/threonine kinase that coordinates genomic stress responses, especially after DNA double-strand breaks.[1][2] In the nervous system, ATM is relevant because neurons are long-lived, post-mitotic cells that must continuously repair DNA damage without dilution through cell division.[3][4]
Biallelic pathogenic variants in ATM cause ataxia-telangiectasia, a multisystem disorder with progressive cerebellar neurodegeneration, immunodeficiency, radiosensitivity, and increased cancer risk.[3:1][5] Beyond Mendelian disease, ATM signaling intersects with oxidative stress, mitochondrial quality control, and inflammatory pathways that are mechanistically relevant across neurodegenerative disorders.[4:1][6]
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.[2:1][7]
Major response outputs include:
In neural tissue, these outputs shift toward survival-vs-death decisions because mature neurons do not re-enter canonical proliferative checkpoints safely.[4:2]
ATM also responds to oxidative stress and helps shape antioxidant responses and mitochondrial fitness, including links to mitophagy-related pathways.[4:3][8] This is relevant to neurodegeneration because oxidative injury and impaired mitochondrial quality control are shared stressors across tauopathy, synucleinopathy, and motor neuron disease pathways.[6:1][8:1]
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.[3:2][5:1] Proposed contributors include:
ATM perturbation also affects astrocyte stress responses, including oxidative and endoplasmic-reticulum stress states that can amplify non-cell-autonomous injury to neurons.[9] This places ATM at a gene-to-cell-state interface relevant for neuroinflammation and glia-neuron feed-forward loops.
This is the best-established ATM neurodegenerative phenotype. Hallmarks include progressive cerebellar ataxia, oculomotor abnormalities, peripheral neuropathy, systemic immune defects, and marked radiosensitivity.[3:3][5:2] The disorder is a direct human model linking deficient DNA-damage signaling to progressive neurodegeneration.
ATM is not a major monogenic Parkinson's gene, but heterozygous variation and pathway-level dysfunction may influence dopaminergic vulnerability in subsets of patients.[6:2][10] Mechanistic overlap is strongest in DNA-repair stress, mitochondrial dysfunction, and oxidative injury convergence rather than a single deterministic ATM-PD axis.[6:3][8:2]
AD brains show chronic DNA damage burden and altered stress signaling; ATM pathway dysregulation has been discussed as a contributing modifier of neuronal resilience.[6:4][11] Current evidence supports ATM as a biologically plausible vulnerability node rather than a standalone primary AD driver.
Potential translational readouts include:
These remain investigational and are not currently routine clinical biomarkers in dementia care.[6:5][11:1]
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:
Any direct ATM modulation strategy must account for oncologic and genomic-stability tradeoffs.[4:4][6:6]
Gatti RA, Berkel I, Boder E, et al. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature. 1988. ↩︎
Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science. 1995. ↩︎ ↩︎
Rothblum-Oviatt C, Wright J, Lefton-Greif MA, et al. Ataxia telangiectasia: a review. Orphanet Journal of Rare Diseases. 2016. ↩︎ ↩︎ ↩︎ ↩︎
Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nature Reviews Molecular Cell Biology. 2013. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Nahhas N, Conklin LS, Dunaway S, et al. Neurodegeneration in ataxia-telangiectasia. Annals of Neurology. 2022. ↩︎ ↩︎ ↩︎
Madabhushi R, Pan L, Tsai LH. DNA damage and its links to neurodegeneration. Neuron. 2014. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003. ↩︎
Valentin-Vega YA, Maclean KH, Tait-Mulder J, et al. Mitochondrial dysfunction in ataxia-telangiectasia. Blood. 2012. ↩︎ ↩︎ ↩︎
Barlow C, Dennery PA, Shigenaga MK, et al. Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs. Proceedings of the National Academy of Sciences USA. 1999. ↩︎
Lee JH, Mand MR, Kao CH, et al. ATM directs DNA damage responses and proteostasis in neurons to maintain homeostasis. Nature Reviews Neurology. 2017. ↩︎
Suberbielle E, Djukic B, Evans M, et al. DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice. Nature Communications. 2015. ↩︎ ↩︎