Decoding the Genetic Roots of Brain Aneurysms: Unveiling the Intriguing Secrets within Our Minds

Scientists at the RIKEN Center for Brain Science (CBS) in Japan have made a groundbreaking discovery, unraveling a series of genetic mutations responsible for the development of intracranial aneurysms. These abnormal dilations of blood vessels in the brain pose a significant risk of rupture at any given time. By focusing on a shared biological signaling pathway affected by these mutations, the researchers have successfully identified the first-ever pharmaceutical treatment that counteracts this signaling. Their findings were recently published in Science Translational Medicine on June 14.

Approximately 5% of the population carries unruptured intracranial aneurysms on the brain’s surface, characterized by weakened arterial walls resembling swollen arteries. Often, these aneurysms go unnoticed until a rupture occurs, leading to severe and potentially fatal bleeding around the brain. Surgical intervention remains the primary treatment option, but it carries its own inherent risks, especially when the aneurysm is located in a sensitive area. Consequently, the pursuit of alternative non-surgical approaches has become a top priority. As the RIKEN CBS team embarked on investigating the origins of intracranial aneurysms, they discovered a potential avenue for treatment.

Intracranial aneurysms manifest in two forms, namely intracranial fusiform aneurysms (IFAs) and intracranial saccular aneurysms (ISAs), with ISAs accounting for approximately 90% of cases. While previous studies had reported mutations in IFA arteries, the origins of the more prevalent ISA type remained enigmatic. To address this critical gap in knowledge, the RIKEN team meticulously sequenced the entire exomes, encompassing the DNA segments responsible for protein synthesis, in cells derived from 65 aneurysmal arteries and 24 normal arteries. Additionally, through extensive targeted sequencing, they identified six genes shared by both IFAs and ISAs, absent in non-aneurysmal arteries, alongside ten genes unique to either IFAs or ISAs. While factors like age, hypertension, and alcohol consumption elevate the risk of intracranial aneurysms, Hirofumi Nakatomi, the project leader at RIKEN CBS, notes that “the surprising discovery that more than 90% of aneurysms had mutations in a common set of 16 genes suggests that somatic mutation could be the primary trigger in most cases.”

Further investigations revealed that all six genes common to both IFAs and ISAs induced aberrant activation of the NF-κB biological signaling pathway. Consequently, the subsequent focus involved comprehending the intricacies of these mutations and devising a means to inhibit the abnormal signaling. Initially, they traced mutations in one of the six genes, PDGDRB, across different layers of human aneurysm samples. Subsequently, by linking the PDGDRB mutation to heightened cell migration and inflammation in cultured cells, the researchers discovered that these effects could be nullified through sunitinib, a drug that impedes the modified PDGDRB signaling.

To further validate their findings, the researchers engineered a mouse model to simulate intracranial aneurysms. They achieved this by introducing a mutant form of PDGFRB into the basilar artery, located at the base of the brain, using an adenovirus. After a month, the artery’s diameter had doubled, and its structure had become severely compromised. Similar to the results obtained in cultured cells, administering sunitinib to the mice counteracted the effects of the mutant gene. Consequently, their basilar arteries retained their normal size and strength. Nakatomi states, “Creating the first non-surgical animal model of intracranial aneurysm is a notable achievement in itself, but more significantly, we were able to suppress artery expansion through drug intervention, demonstrating the potential for pharmacological treatment of intracranial aneurysms.”

While further research is necessary to confirm the effectiveness of this drug treatment in human patients, the true challenge lies in detection. Nakatomi explains, “Unruptured intracranial aneurysms are typically detected through Magnetic Resonance Angiography or Computed Tomography Angiography during routine health checkups. Without access to these tests, aneurysms remain undetectable until they rupture.” In Japan, where this study was conducted, many individuals undergo these tests as part of their annual health assessments, making the development of drug treatments all the more valuable.

Reference: “Increased PDGFRB and NF-κB signaling caused by highly prevalent somatic mutations in intracranial aneurysms” by Yasuyuki Shima, Shota Sasagawa, Nakao Ota, Rieko Oyama, Minoru Tanaka, Mie Kubota-Sakashita, Hirochika Kawakami, Mika Kobayashi, Naoko Takubo, Atsuko Nakanishi Ozeki, Xiaoning Sun, Yeon-Jeong Kim, Yoichiro Kamatani, Koichi Matsuda, Kazuhiro Maejima, Masashi Fujita, Kosumo Noda, Hiroyasu Kamiyama, Rokuya Tanikawa, Motoo Nagane, Junji Shibahara, Toru Tanaka, Yoshiyuki Rikitake, Nobuko Mataga, Satoru Takahashi, Kenjiro Kosaki, Hideyuki Okano, Tomomi Furihata, Ryo Nakaki, Nobuyoshi Akimitsu, Youichiro Wada, Toshihisa Ohtsuka, Hiroki Kurihara, Hiroyuki Kamiguchi, Shigeo Okabe, Masato Nakafuku, Tadafumi Kato, Hidewaki Nakagawa, Nobuhito Saito and Hirofumi Nakatomi, 14 June 2023, Science Translational Medicine.
DOI: 10.1126/scitranslmed.abq7721

Frequently Asked Questions (FAQs) about Brain aneurysms

More about Brain aneurysms

• RIKEN Center for Brain Science (CBS): Official Website
• Science Translational Medicine: Journal Article
• National Institute of Neurological Disorders and Stroke: Intracranial Aneurysms Information Page
• Sunitinib: Drug Information
• Magnetic Resonance Angiography (MRA): RadiologyInfo
• Computed Tomography Angiography (CTA): RadiologyInfo