Dear Friends,
I’m excited to share breaking news about a new paper just published by Paige Burrell and colleagues in Michael Kastan’s lab at Duke University that sheds important new light on ataxia-telangiectasia (A-T), and more broadly on how the ATM gene functions in human biology.
A-T is caused by having two non-working copies of the ATM gene and leads to progressive loss of coordination, immune dysfunction, increased cancer risk, and lung disease. For decades, ATM has been viewed almost entirely as a DNA damage repair protein, and many A-T symptoms have been assumed to stem from failed DNA repair alone.
This paper shows that the ATM protein does much more.
With funding from the A-T Children’s Project, the authors discovered that ATM directly regulates another protein called GRP94, which helps control how certain cell signaling receptors are processed and displayed on the surface of cells. When ATM is functioning normally, it keeps GRP94 activity tightly controlled. When ATM is missing, as in A-T, GRP94 accumulates at the cell surface.
That turns out to matter a lot.
Excess cell-surface GRP94 stabilizes growth-factor receptors, including EGFR and IGF-1R, causing them to signal too strongly. In immune cells of the brain (microglia), loss of ATM also leads to excessive activation, increased inflammatory signaling, and heightened phagocytic activity. Importantly, the team showed that blocking GRP94 at the cell surface reverses many of these abnormalities, even when ATM itself is absent.
The therapeutic hypothesis that emerges is compelling.
Rather than trying to directly replace or repair ATM, a large and difficult gene, it may be possible to reduce inflammation, abnormal signaling, and neurodegeneration in A-T by selectively inhibiting cell-surface GRP94, a downstream driver of pathology.
This work doesn’t claim a cure, and much remains to be tested, especially in animal models and humans. But it provides a concrete, mechanistic explanation for several A-T features that DNA damage alone cannot fully explain, and it opens a new, potentially druggable path for life-improving therapies.
It’s also worth noting the scientific lineage behind this work. Mike Kastan has been a leader in cancer biology for decades and played a central role in defining how cells sense DNA damage and activate tumor suppressor pathways such as p53, helping to establish ATM as a key regulator of genome stability and cancer risk and shaping entire fields of cancer research while influencing modern cancer therapy.
For families, scientists, and drug developers working in A-T and potentially many related diseases, this news from Mike’s team feels like an important and hopeful step forward.
All the best,
Brad
Brad Margus, Founder, Volunteer Board Chair and A-T Dad