Zespół delecji 22q11.2 (22q) zwiększa ryzyko schizofrenii z powodu wad rozwojowych czaszki powiązanych z genem Tbx1, wpływającym na rozwój móżdżku. To podkreśla, jak czynniki niezwiązane z mózgiem, takie jak defekty kości, mogą wpływać na zaburzenia neurologiczne.
Zespół delecji chromosomalnej 22q11.2 (22q) okazał się jednym z najsilniejszych czynników ryzyka schizofrenii. Naukowcy ze Szpitala Badawczego Dziecięcego St. Jude zidentyfikowali zniekształcone obszary móżdżku zarówno w modelach laboratoryjnych, jak i u pacjentów z 22q, przypisując te deformacje nieprawidłowemu tworzeniu czaszki.
Ponadto naukowcy powiązali wadę rozwojową czaszki z utratą pojedynczego genu: Tbx1. Badanie to podkreśla, że zaburzenia neurologiczne mogą mieć źródła poza układem nerwowym, takie jak wady rozwojowe czaszki. Wyniki opublikowano w Previous work from Zakharenko found that the deletion of only one 22q gene, Dgcr8, disrupts the flow of auditory information from a lower brain region called the thalamus to the auditory cortex, where sounds are interpreted. This region of the brain is also associated with auditory hallucinations, which are a hallmark symptom of schizophrenia. The researchers called this breakdown in information flow “thalamocortical disruption.”
“Although thalamocortical disruption occurs late in development, which is consistent with the onset of schizophrenia symptoms, it stays and doesn’t go away. However, hallucinations are transient in nature — they come and go,” Zakharenko said. “It seemed that this was just one of the hits that triggered symptoms. The question is: What is the other hit?”
The researchers noticed a part of the brain, the cerebellum, malformed in 22q animal models, specifically, the cerebellum’s small lobules called the flocculus and paraflocculus. Most neurodevelopmental disorders arise from defects in genes that play a role in the brain, but the 22q gene the researchers linked to this malformation, Tbx1, was unexpected.
“What is interesting about Tbx1 is that it is not very well expressed in the brain, especially adolescent or adult brain,” Zakharenko said. “Rather, it’s expressed in the surrounding tissues, namely bone, cartilage, and vasculature tissues. It is very unlikely that Tbx1 directly affects the brain at all.”
Instead, removing Tbx1 has an indirect but significant effect on brain development. Bone formation relies on immature osteoblast cells correctly growing into mature osteocytes. Tbx1 removal disrupted this cycle, resulting in an underdeveloped pocket in the skull which normally houses the flocculus and paraflocculus. For a neurological syndrome, the findings are strikingly unusual — with no pocket in the skull for these structures to develop, they appear substantially smaller than normal. The reduction of the flocculus and paraflocculus was validated through magnetic resonance imaging studies of dozens of patients with 22q and a comparative control group.
Misshapen skull removes cerebellum’s checks and balances
Zakharenko’s team studied the flocculus and paraflocculus’ role in the brain to better understand how their malformation could influence behavior. “We found that the neural circuits within the flocculus and paraflocculus are dysfunctional,” explained Zakharenko.
The regions also control a reflex that ensures stable vision during head movements and is crucial for face recognition. The researchers found that this reflex is impaired in 22q. This may be a valuable lead for schizophrenia research because patients with schizophrenia have a deficit in face recognition.
The paraflocculus is also connected to the auditory cortex. However, the details of such connectivity are unclear. Zakharenko hopes future research will more clearly reveal the links between 22q and schizophrenia. More specifically, he hopes that future research will illuminate how the paraflocculus affects the function of the auditory cortex and provide us with the second hit that leads to hallucinations.
“In my mind, it’s like a stepping stone. We hope to follow this chain of events from the malformed skull to the underdeveloped flocculus and paraflocculus to the auditory cortex dysfunction,” Zakharenko said. “This would be extraordinary because it all started with a bone.”
Reference: “Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome” by Tae-Yeon Eom, J. Eric Schmitt, Yiran Li, Christopher M. Davenport, Jeffrey Steinberg, Audrey Bonnan, Shahinur Alam, Young Sang Ryu, Leena Paul, Baranda S. Hansen, Khaled Khairy, Stephane Pelletier, Shondra M. Pruett-Miller, David R. Roalf, Raquel E. Gur, Beverly S. Emanuel, Donna M. McDonald-McGinn, Jesse N. Smith, Cai Li, Jason M. Christie, Paul A. Northcott and Stanislav S. Zakharenko, 5 December 2024, Nature Communications.
DOI: 10.1038/s41467-024-54837-3
The study was supported by grants from the National Cancer Institute at the National Institutes of Health (R01 CA261898, R01 CA216354, R21 CA261833, U24 CA55727, U01 CA195547 and Cancer Center Support [CORE] Grant CA21765) oraz amerykańską libańsko-syryjską stowarzyszoną organizację charytatywną (ALSAC), organizację zbierającą fundusze i podnoszącą świadomość św. Judy.
