Unravelling HGprt functioning in fore- and midbrain development using brain organoids
Awardee: Sharon Kolk
Institution: Radboud University, Donders Institute for Neuroscience
Grant Amount: $68,367.00
Funding Period: February 1, 2024 - January 31, 2025
Summary:
LND is an incapacitating disease characterized by a neurobehavioral phenotype, cognitive deficits and self-injurious behavior caused by HPRT1 gene mutation(s). LND is specifically associated with a reduction of dopamine in the brain. Recently, we reported that proliferation and migration patterns of developing midbrain dopamine (mDA) neurons are disrupted in absence of the gene, resulting in abnormal brain development in an LND animal model. To dissect the role of the causative gene in human fore- and midbrain development, we intend to investigate human-specific brain organoids using patient-derived induced pluripotent stem cell (iPSC) lines carrying HGPRT loss-of-function (LOF) mutations, age-matched control lines as well as edited control lines carrying HGPRT mutations. In addition, assembloids -fusions of dorsal forebrain organoids and midbrain organoids- will be generated in various combinations of control versus LOF tissue at multiple time points. It is furthermore shown that folic acid plays a role in purine metabolism and that physiological levels lead to metabolite accumulation in LND patients. Therefore, we will add various concentrations to the culture medium of both the fore-as well as the midbrain organoids at multiple developmental timepoints. Eventually this will give us insight into the developmental time window where we can, either genetically or pharmacologically, intervene in the future to alleviate particularly the behavioral and/or cognitive characteristics associated with LND.