Is CADASIL a Risk for Prolonged Spaceflight in NOTCH3 Mutation Carriers?: An OMICS Based Exploration of Neurovascular Vulnerability in Space

Faculty Mentor Information

Dr. Nilufar Ali, Boise State University

Presentation Date

7-2025

Abstract

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant vascular disorder caused by mutations in the epidermal growth factor-like repeat (EGFr) domain of the NOTCH3 extracellular domain (ECD). These mutations result in either gain or loss of cysteine residues in the NOTCH3-ECD, predisposing it to abnormal aggregation via disulfide bonds with both mutant and wild-type NOTCH3-ECDs1-3. The accumulation of these aggregates leads to vascular smooth muscle cell (VSMC) degeneration and progressive arterial fibrosis, thickening, and luminal narrowing, particularly in cerebral vessels4. CADASIL typically presents in mid-adulthood and worsens with age5. While NOTCH3-ECD accumulation defines the pathology, the canonical NOTCH3 signaling pathway remains mostly unaffected. Hypoxic conditions significantly upregulate NOTCH3 expression in mice6, and oxidative stress elevates NOTCH3 levels—a process reversed by antioxidants7. While CADASIL is a genetic disorder, its clinical expression and progression are significantly influenced by age. Spaceflight environments are known to induce systemic oxidative stress, impair proteostasis, and accelerate aging-related molecular changes8-10.

Hypothesis: We hypothesize that the spaceflight environment—characterized by radiation, microgravity, increased oxidative stress, hypoxia, and hypercapnia—may exacerbate CADASIL pathology in asymptomatic NOTCH3 mutation carriers by promoting increased NOTCH3 expression and protein aggregation, potentially leading to earlier clinical manifestation.

Objective: To explore this hypothesis, we performed a comparative pathway-level analysis using publicly available proteomic datasets from CADASIL patients vs. healthy controls11, and astronauts post- vs. pre-spaceflight12. We specifically evaluated overlap in NOTCH3-related pathways and stress-response mechanisms.

Results: Our analysis revealed a significant overlap in both upregulated and downregulated pathways between CADASIL and post-spaceflight samples, particularly in immune activation, extracellular matrix remodeling, and neurodevelopmental suppression. Importantly, we observed consistent post-flight upregulation of NOTCH3, which has been linked to toxic protein aggregation and disease progression3. These findings suggest that spaceflight-induced stressors could act as disease accelerants in NOTCH3 mutation carriers.

Conclusion: These observations raise concerns about the potential risks of long-duration spaceflight for individuals with pathogenic NOTCH3 variants. However, they also present a unique opportunity: the extreme physiological stress and accelerated aging associated with spaceflight offers a powerful platform for modeling genetically driven neurovascular diseases like CADASIL and testing targeted interventions. Furthermore, these findings underscore the importance of integrating precision medicine approaches—including genomic screening, biomarker monitoring, and individualized risk stratification—into astronaut selection and health management protocols. Such practices are currently limited to commercial spaceflight operations and remain underutilized in governmental space agencies.

References:

  1. Schoemaker, D. & Arboleda-Velasquez, J. F. Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases. Am J Pathol 191, 1856-1870 (2021). https://doi.org:10.1016/j.ajpath.2021.03.015
  2. Haile, S., Balzer, B. C., Egan, E., Jorcyk, C. L. & Ali, N. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL): Immunotherapy and Cell Therapy approaches. arXiv preprint arXiv:2506.09293 (2025).
  3. Dupre, N. et al. Protein aggregates containing wild-type and mutant NOTCH3 are major drivers of arterial pathology in CADASIL. J Clin Invest 134 (2024). https://doi.org:10.1172/JCI175789
  4. Wang, T., Baron, M. & Trump, D. An overview of Notch3 function in vascular smooth muscle cells. Prog Biophys Mol Biol 96, 499-509 (2008). https://doi.org:10.1016/j.pbiomolbio.2007.07.006
  5. Meschia, J. F. et al. Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association. Stroke 54, e452-e464 (2023). https://doi.org:10.1161/STR.0000000000000444
  6. Yu, Y. R., Mao, L., Piantadosi, C. A. & Gunn, M. D. CCR2 deficiency, dysregulation of Notch signaling, and spontaneous pulmonary arterial hypertension. Am J Respir Cell Mol Biol 48, 647-654 (2013). https://doi.org:10.1165/rcmb.2012-0182OC
  7. Zhang, X. et al. N-acetylcysteine negatively regulates Notch3 and its malignant signaling. Oncotarget 7, 30855-30866 (2016). https://doi.org:10.18632/oncotarget.8806
  8. Ali, N., Beheshti, A. & Hampikian, G. Space exploration and risk of Parkinson's disease: a perspective review. NPJ Microgravity 11, 1 (2025). https://doi.org:10.1038/s41526-024-00457-6
  9. Brandner, M. & Ali, N. Studying Parkinson's Disease-Like Molecular Changes in Dopaminergic Neurons Exposed to Simulated Microgravity. (2025). https://doi.org:https://scholarworks.boisestate.edu/under_showcase_2025/13
  10. Guarnieri, J. W. et al. Guardians of the Mitochondria: Space Mitochondria 2.0 Systemic Analysis Reveals Bioenergetic Dysregulation Across Species. https://doi.org:https://dx.doi.org/10.2139/ssrn.5087025
  11. Menendez-Valladares, P. et al. A Search for New Biological Pathways in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy by Proteomic Research. J Clin Med 13 (2024). https://doi.org:10.3390/jcm13113138
  12. Overbey, E. G. et al. The Space Omics and Medical Atlas (SOMA) and international astronaut biobank. Nature 632, 1145-1154 (2024). https://doi.org:10.1038/s41586-024-07639-y

Comments

Frederick Sanders@,1,2, Colette Mardirossian1,2, Samuel Ward1,2, Mathew Brandner2, Max-Florian Mortimer2, Mukta Sane2, Nilufar Ali*,2 1 Idaho College of Osteopathic Medicine, Meridian, Idaho, USA 2 Department of Biological Sciences, Boise State University, Boise, Idaho, USA *Corresponding author- nilufarali@boisestate.edu @ Presenting author

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Is CADASIL a Risk for Prolonged Spaceflight in NOTCH3 Mutation Carriers?: An OMICS Based Exploration of Neurovascular Vulnerability in Space

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant vascular disorder caused by mutations in the epidermal growth factor-like repeat (EGFr) domain of the NOTCH3 extracellular domain (ECD). These mutations result in either gain or loss of cysteine residues in the NOTCH3-ECD, predisposing it to abnormal aggregation via disulfide bonds with both mutant and wild-type NOTCH3-ECDs1-3. The accumulation of these aggregates leads to vascular smooth muscle cell (VSMC) degeneration and progressive arterial fibrosis, thickening, and luminal narrowing, particularly in cerebral vessels4. CADASIL typically presents in mid-adulthood and worsens with age5. While NOTCH3-ECD accumulation defines the pathology, the canonical NOTCH3 signaling pathway remains mostly unaffected. Hypoxic conditions significantly upregulate NOTCH3 expression in mice6, and oxidative stress elevates NOTCH3 levels—a process reversed by antioxidants7. While CADASIL is a genetic disorder, its clinical expression and progression are significantly influenced by age. Spaceflight environments are known to induce systemic oxidative stress, impair proteostasis, and accelerate aging-related molecular changes8-10.

Hypothesis: We hypothesize that the spaceflight environment—characterized by radiation, microgravity, increased oxidative stress, hypoxia, and hypercapnia—may exacerbate CADASIL pathology in asymptomatic NOTCH3 mutation carriers by promoting increased NOTCH3 expression and protein aggregation, potentially leading to earlier clinical manifestation.

Objective: To explore this hypothesis, we performed a comparative pathway-level analysis using publicly available proteomic datasets from CADASIL patients vs. healthy controls11, and astronauts post- vs. pre-spaceflight12. We specifically evaluated overlap in NOTCH3-related pathways and stress-response mechanisms.

Results: Our analysis revealed a significant overlap in both upregulated and downregulated pathways between CADASIL and post-spaceflight samples, particularly in immune activation, extracellular matrix remodeling, and neurodevelopmental suppression. Importantly, we observed consistent post-flight upregulation of NOTCH3, which has been linked to toxic protein aggregation and disease progression3. These findings suggest that spaceflight-induced stressors could act as disease accelerants in NOTCH3 mutation carriers.

Conclusion: These observations raise concerns about the potential risks of long-duration spaceflight for individuals with pathogenic NOTCH3 variants. However, they also present a unique opportunity: the extreme physiological stress and accelerated aging associated with spaceflight offers a powerful platform for modeling genetically driven neurovascular diseases like CADASIL and testing targeted interventions. Furthermore, these findings underscore the importance of integrating precision medicine approaches—including genomic screening, biomarker monitoring, and individualized risk stratification—into astronaut selection and health management protocols. Such practices are currently limited to commercial spaceflight operations and remain underutilized in governmental space agencies.

References:

  1. Schoemaker, D. & Arboleda-Velasquez, J. F. Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases. Am J Pathol 191, 1856-1870 (2021). https://doi.org:10.1016/j.ajpath.2021.03.015
  2. Haile, S., Balzer, B. C., Egan, E., Jorcyk, C. L. & Ali, N. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL): Immunotherapy and Cell Therapy approaches. arXiv preprint arXiv:2506.09293 (2025).
  3. Dupre, N. et al. Protein aggregates containing wild-type and mutant NOTCH3 are major drivers of arterial pathology in CADASIL. J Clin Invest 134 (2024). https://doi.org:10.1172/JCI175789
  4. Wang, T., Baron, M. & Trump, D. An overview of Notch3 function in vascular smooth muscle cells. Prog Biophys Mol Biol 96, 499-509 (2008). https://doi.org:10.1016/j.pbiomolbio.2007.07.006
  5. Meschia, J. F. et al. Management of Inherited CNS Small Vessel Diseases: The CADASIL Example: A Scientific Statement From the American Heart Association. Stroke 54, e452-e464 (2023). https://doi.org:10.1161/STR.0000000000000444
  6. Yu, Y. R., Mao, L., Piantadosi, C. A. & Gunn, M. D. CCR2 deficiency, dysregulation of Notch signaling, and spontaneous pulmonary arterial hypertension. Am J Respir Cell Mol Biol 48, 647-654 (2013). https://doi.org:10.1165/rcmb.2012-0182OC
  7. Zhang, X. et al. N-acetylcysteine negatively regulates Notch3 and its malignant signaling. Oncotarget 7, 30855-30866 (2016). https://doi.org:10.18632/oncotarget.8806
  8. Ali, N., Beheshti, A. & Hampikian, G. Space exploration and risk of Parkinson's disease: a perspective review. NPJ Microgravity 11, 1 (2025). https://doi.org:10.1038/s41526-024-00457-6
  9. Brandner, M. & Ali, N. Studying Parkinson's Disease-Like Molecular Changes in Dopaminergic Neurons Exposed to Simulated Microgravity. (2025). https://doi.org:https://scholarworks.boisestate.edu/under_showcase_2025/13
  10. Guarnieri, J. W. et al. Guardians of the Mitochondria: Space Mitochondria 2.0 Systemic Analysis Reveals Bioenergetic Dysregulation Across Species. https://doi.org:https://dx.doi.org/10.2139/ssrn.5087025
  11. Menendez-Valladares, P. et al. A Search for New Biological Pathways in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy by Proteomic Research. J Clin Med 13 (2024). https://doi.org:10.3390/jcm13113138
  12. Overbey, E. G. et al. The Space Omics and Medical Atlas (SOMA) and international astronaut biobank. Nature 632, 1145-1154 (2024). https://doi.org:10.1038/s41586-024-07639-y