Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in
the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual
disability, behavioral disorders, language delay, and seizures. In this work, we generated
human brain organoids from induced pluripotent stem cells of healthy subjects and
CTD patients. Brain organoids from CTD donors had reduced creatine uptake compared
with those from healthy donors. The expression of neural progenitor cell markers SOX2
and PAX6 was reduced in CTD-derived organoids, while GSK3β, a key regulator of neurogenesis,
was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical
analysis identified changes in the abundance of proteins associated with intellectual
disability, epilepsy, and autism. Re-establishment of the expression of a functional
SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression
of SOX2, GSK3β, and other key proteins associated with clinical features of CTD patients.
Our brain organoid model opens new avenues for further characterizing the CTD pathophysiology
and supports the concept that reinstating creatine levels in patients with CTD could
result in therapeutic efficacy.
