Abstract
In this article, you will discover how studying one unusual family led us to identify CADASIL, a genetic disease that damages the brain’s small blood vessels. You will learn how we found that changes in a protein called NOTCH3 cause it to build up around these vessels, forming clumps that lead to the loss of important vessel cells. You will also explore how this discovery helped solve a 25-year mystery about how the disease works. Finally, you will read about the biggest open questions in the field and how this research is guiding new treatments and helping us understand many other brain diseases.
Doctor Anne Joutel won the Brain Prize in 2019, together with Professors Marie-Germaine Bousser, Hugues Chabriat, and Elisabeth Tournier-Lasserve “for their groundbreaking work on the causes of CADASIL, the most common hereditary form of stroke”.
The Brain Prize is an international award that recognizes and celebrates highly original and groundbreaking advances in any area of brain research, from basic neuroscience to applied clinical research. Since it was founded in 2011 and up until 2025, The Brain Prize has been awarded to 49 scientists from 11 countries.
A Medical Mystery That Changed My Career
For as long as I can remember, I wanted to be a physician. I was fascinated by our family doctor’s work and dreamed of becoming a neurologist. Near the end of my training, I met two enthusiastic neurologists who had discovered something very unusual: a large family in which many people had repeated strokes, damage to their brain’s white matter, and later dementia—even though they were otherwise healthy and had none of the usual risk factors like high blood pressure or smoking. When the neurologists checked younger relatives who seemed healthy, they found that some already had white-matter changes long before any symptoms appeared (Figure 1). When we eventually examined one family member’s brain, we saw severe damage in the small blood vessels, showing that something was going wrong long before the strokes happened. This led us to realize we had discovered a new genetic disease that affects the brain’s small blood vessels—now called CADASIL [1, 2].
- Figure 1 - The discovery of CADASIL.
- (A) Near the end of my medical training, I met two neurologists who were caring for people with unexplained brain problems. (B) When they examined many members of one family, the neurologists discovered that even young relatives who felt healthy already showed early signs of brain changes. (C) These changes were seen in the brain’s white matter (1), which gets damaged over time (2, 3). This was key clue that helped reveal a new genetic disease—now known as CADASIL.
This discovery completely changed my career. Instead of becoming a doctor who only sees patients, I found myself drawn into scientific research. What started as a medical mystery opened up many exciting questions, and I soon realized how much I enjoyed investigating them in the lab. Twenty-five years later, I am still fascinated by this work. I am still making new discoveries and working closely with doctors to better understand and treat CADASIL.
What is CADASIL?
CADASIL is a genetic disease that affects small blood vessels in the brain. A genetic disease is a condition caused by changes in genes that can be passed from parents to children. CADASIL is caused by mutations in a gene that called NOTCH3 [3]. Mutations in NOTCH3 are the most frequent genetic cause of diseases affecting small blood vessels in the brain. CADASIL affects at least two to six people in every 100,000 people. Among relatively young adults who suffer from strokes, CADASIL accounts for approximately 2% of those cases.
Recent discoveries have been game changing, as it was found that CADASIL-type mutations occur in about one to two people per 1,000—much more frequent than we thought! These mutations increase the risk of brain conditions such as stroke and dementia. This finding is incredibly important because it shows that working on CADASIL may have strong implications for understanding other diseases that involve small blood vessels.
What Goes Wrong in the Blood Vessels?
There are three main types of blood vessels in the brain: arteries, which carry blood from the brain to the body; veins, which carry blood from the body back to the heart; and tiny capillaries, where the exchange of nutrients and wastes occurs. CADASIL affects all of these vessels. Together, we call them “small vessels” to distinguish them from very large vessels like the carotid artery in the neck, but they are not actually that small—just smaller than other blood vessels that are known to be involved in strokes.
In CADASIL, the small blood vessels in the brain start to change in three important ways (Figure 2). First, the smooth muscle cells that normally wrap around the vessels begin to die, making the vessels weaker. Second, the vessel walls lose their flexibility and become stiff. These two problems happen in many small-vessel diseases.
- Figure 2 - Blood vessels in CADASIL.
- (A) In CADASIL, the small blood vessels in the brain become damaged over time. (B) These vessels include arteries (1), arterioles (2), and capillaries (3). (C) Two problems found in CADASIL also appear in other small-vessel diseases: the loss of smooth muscle cells (1) and a reduction in how flexible the vessels are (2). What makes CADASIL unique is the presence of dark clumps of protein called GOM deposits, which build up on the outside of the vessels (3).
But CADASIL has one special feature: tiny clumps of protein called granular osmiophilic material (GOM) deposits that stick to the outside of the blood vessel cells [4]. These clumps are so small that doctors can only see them with a super-powerful electron microscope. If doctors spot these GOM deposits, it is a clear sign that the person has CADASIL. These clumps also appear in the skin’s blood vessels, which is why doctors used to take a tiny skin sample to diagnose CADASIL before modern genetic tests became available.
Understanding the NOTCH3 Protein
NOTCH3 is a large protein found mainly in the cells that wrap around small blood vessels—smooth muscle cells and supporting cells called pericytes. These cells help keep blood vessels strong and working properly. NOTCH3 acts like a communication switch between neighboring cells: it helps them send signals that tell the cells how to grow, mature, and stay healthy. This signaling is especially important when blood vessels are developing, guiding smooth muscle cells to reach their final shape and function so the vessels become stable and well-organized.
If NOTCH3 is missing, smooth muscle cells do not mature properly, and blood vessels cannot respond correctly to changes in blood pressure. Normally, smooth muscle cells can widen or narrow the vessel to keep blood flowing steadily to the brain. Without NOTCH3, this control system weakens, the cells become unhealthy, and the vessels cannot support the brain as they should.
NOTCH3 is built from repeating parts that include small pieces called cysteines, which pair up to form “bridges” that keep the protein organized. In CADASIL, mutations add or remove one cysteine. This does not greatly change the overall shape of NOTCH3, but it disrupts these bridges, causing the proteins to stick together and form the GOM clumps mentioned earlier.
The Accumulation Problem
For many years, scientists did not know how NOTCH3 mutations caused CADASIL. Some thought the issue was in how NOTCH3 sends messages to smooth muscle cells to guide their proper development and activity, but most mutations do not change this. We already knew that NOTCH3 piled up in GOM deposits around vessels, but we could not prove this buildup harmed smooth muscle cells. Using new tools, my lab recently showed that when NOTCH3 accumulates too much, these cells begin to disappear—and when we reduce the buildup, more cells stay healthy. This proved that NOTCH3 accumulation, not communication problems, causes smooth muscle cells to fail and die, finally solving a 25-year-old question!
Open Research Questions in CADASIL and Beyond
Even after many years of studying CADASIL, scientists still have big questions to answer. One of the biggest is how the extra buildup of NOTCH3 actually causes the smooth muscle cells in blood vessels to die—something my lab is working on right now. We also do not fully understand how problems in the vessels, like stiffness or leaks, turn into the tiny strokes seen in CADASIL. In terms of white-matter damage, we think the brain may not get enough steady blood flow, but the full story is still a mystery. Another open question is what NOTCH3 does in adult blood vessels, since we mainly understand its job in young people.
Scientists also want to know why smooth muscle cells are lost in many different small-vessel diseases, not just CADASIL, and whether the same process happens in all of them. Finding these answers could help explain a large number of strokes and many memory problems that happen as people get older. CADASIL gives us a powerful model to explore these puzzles and discover new ways to help protect the brain.
Current Treatments and Future Directions
Today, the most important treatments for CADASIL are simple but very effective: do not smoke and keep blood pressure under control (Figure 3). Even though CADASIL is a genetic disease, these steps have already helped many people stay healthier over the last 20 years. For patients who have already had a stroke, doctors sometimes give medicines that help prevent unwanted clumps of blood cells from forming inside blood vessels. These medicines work well for other kinds of strokes, so doctors hope they may help prevent new strokes in CADASIL too—but scientists still need to test how well they work for this disease.
- Figure 3 - Treating CADASIL.
- Today, the best way to care for CADASIL is to (A) avoid smoking and (B) to keep blood pressure under control. (C) Scientists are also developing future treatments that may reduce the amount of NOTCH3 protein in the brain. (D) The goal is to stop NOTCH3 from building up into GOM deposits, which damage the brain’s small blood vessels.
For the future, scientists are exploring an exciting new idea: using special molecules called antisense oligonucleotides to lower the amount of NOTCH3 protein in the blood vessels. These molecules are short pieces of genetic material that can stick to the instructions (RNA) that cells use to make NOTCH3, telling the cell to make less of this protein. By reducing how much NOTCH3 is produced, scientists hope to prevent it from building up into harmful clumps and damaging the vessels.
The big challenge is finding the right balance—reducing NOTCH3 enough to stop the buildup, but not so much that the protein cannot do its normal job of helping blood vessels stay healthy. If this approach works, it could become the first treatment that targets the root cause of CADASIL, rather than just treating its symptoms.
Scientists are also studying ways to help small blood vessels work better—for example, by improving how they control blood flow, meaning how they widen or narrow to send blood where it is needed [5]. Another focus is strengthening the blood–brain barrier, a protective wall that controls what can enter the brain from the blood [6]. Researchers are also exploring how to support the brain’s waste-clearing systems, which help remove harmful substances and proteins [7]. While these treatments are still being tested, they offer hope for protecting the brain and, in the future, targeting the root causes of CADASIL.
Advice for Future Scientists
As I mentioned at the start of this article, I never planned to become a scientist—this happened because I seized a wonderful opportunity when I met passionate medical professionals and researchers working on CADASIL, and it completely changed my career. My advice is to be willing to change your plans without hesitation when a good opportunity appears, and to always stay curious.
The possibility of discovering something new about how the brain works is what gets me excited every morning, and I love that my work is always changing from one day to the next. Science is one of the best jobs because you get to search for answers to mysteries, and in the study of the brain’s tiny blood vessels, there are still many puzzles to solve—so there is plenty of room for many more future scientists to join the journey!
Glossary
Neurologist: ↑ A doctor who treats problems of the brain, spinal cord, and nerves.
Stroke: ↑ A medical event where brain cells are damaged and could die because a blood vessel stops working properly.
White Matter: ↑ The brain’s “wiring system” made of long nerve fibers that carry messages between different brain areas.
CADASIL: ↑ A genetic disease that affects the brain’s small blood vessels and can cause migraines, small strokes, and problems in thinking and memory.
NOTCH3: ↑ A protein found on the outside of certain blood vessel cells that helps them develop and stay healthy. When it has a mutation, this could lead to CADASIL.
Smooth Muscle Cells: ↑ Small muscle cells in the body that gently squeeze and relax to control flow—of blood, food, air, or fluids. In blood vessels, they adjust blood flow by changing how wide the vessel is.
Granular Osmiophilic Material (GOM): ↑ Tiny clumps of protein that build up around blood vessels in CADASIL and can be seen with a very powerful microscope.
Antisense Oligonucleotides: ↑ Genetic “messages” that tell cells to slow down or stop making a certain protein.
Conflict of Interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
I wish to thank Or Raphael for conducting the interview that served as the basis for this paper, and for co-authoring the paper, Iris Gat for providing the figures, and Susan Debad for copyediting the manuscript. Anne Joutel’s research is supported by grants from the National Research Agency, France (ANR-20-CE37-0020-01; ANR-22-CE17-0010-01; ANR-22-NEU2-0004-01), the Leducq Foundation for Cardiovascular Research (Leducq Transatlantic Network of Excellence 22CVD01 BRENDA) and Fondation pour la Recherche Médicale (PROJET EQU202203014672).
Further Resources
• The Brain Prize 2019 -CADASIL
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References
[1] ↑ Chabriat, H., Joutel, A., Dichgans, M., Tournier-Lasserve, E., and Bousser, M. G. 2009. Cadasil. Lancet Neurol. 8:643–53. doi: 10.1016/S1474-4422(09)70127-9
[2] ↑ Chabriat, H., Vahedi, K., Bousser, M. G., Iba-Zizen, M. T., Joutel, A., Nibbio, A., et al. 1995. Clinical spectrum of CADASIL: a study of 7 families. Lancet 346:934–9. doi: 10.1016/S0140-6736(95)91557-5
[3] ↑ Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., et al. 1996. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–10. doi: 10.1038/383707a0
[4] ↑ Tikka, S., Mykkänen, K., Ruchoux, M. M., Bergholm, R., Junna, M., Pöyhönen, M., et al. 2009. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain 132:933–9. doi: 10.1093/brain/awn364
[5] ↑ Iadecola, C. 2017. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96:17–42. doi: 10.1016/j.neuron.2017.07.030
[6] ↑ Sweeney, M. D., Sagare, A. P., and Zlokovic, B. V. 2018. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 14:133–50. doi: 10.1038/nrneurol.2017.188
[7] ↑ Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., et al. 2012. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4147ra111. doi: 10.1126/scitranslmed.3003748