Loss of Tousled-Like Kinase 2 Reduces Antioxidative Responses and Disrupts Brain Development
摘要
Haploinsufficiency of tousled-like kinase 2 (TLK2) causes intellectual developmental disorder, autosomal dominant 57, a rare neurodevelopmental disorder with unclear pathomechanism and no effective treatment. Here, we established Drosophila models with neurodevelopmental defects resembling some disease features, such as microcephaly. Further studies suggested that oxidative stress plays a critical role in these models. Mechanistically, Tlk (the fly homolog of TLK2) loss reduces the expression of antioxidative genes via activating transcription factor 4 (ATF4) and its downstream protein, nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional activator of antioxidative genes, in fly neural stem cells (NSCs), thereby disrupting NSC differentiation and causing microcephaly. In patient-derived brain organoids, ATF4, Nrf2, and their downstream antioxidative genes are also downregulated. Agreeing with these data, these organoids exhibited oxidative stress and microcephaly. Combined, our findings suggest that ATF4/Nrf2-mediated antioxidative stress responses play a critical role in TLK2-related disease and may be a therapeutic target.
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