Sterol dysregulation in Smith-Lemli-Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk.

Owing to the need for de novo cholesterol synthesis and cholesterol-enriched structures within the nervous system, cholesterol homeostasis is critical to neurodevelopment. Diseases caused by genetic disruption of cholesterol biosynthesis, such as Smith-Lemli-Opitz syndrome, which is caused by mutations in 7-dehydrocholesterol reductase (DHCR7), frequently result in broad neurological deficits. Although astrocytes regulate multiple neural processes ranging from cell migration to network-level communication, immunological activation of astrocytes is a hallmark pathology in many diseases. However, the impact of DHCR7 on astrocyte function and immune activation remains unknown. We demonstrate that astrocytes from Dhcr7 mutant mice display hallmark signs of reactivity, including increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Transcript analyses demonstrate extensive Dhcr7 astrocyte immune activation, hyper-responsiveness to glutamate stimulation and altered calcium flux. We further determine that the impacts of Dhcr7 are not astrocyte intrinsic but result from non-cell-autonomous effects of microglia. Our data suggest that astrocyte-microglia crosstalk likely contributes to the neurological phenotypes observed in disorders of cholesterol biosynthesis. Additionally, these data further elucidate a role for cholesterol metabolism within the astrocyte-microglia immune axis, with possible implications in other neurological diseases.

iPSC modeling of rare pediatric disorders.

Discerning the underlying pathological mechanisms and the identification of therapeutic strategies to treat individuals affected with rare neurological diseases has proven challenging due to a host of factors. For instance, rare diseases affecting the nervous system are inherently lacking in appropriate patient sample availability compared to more common diseases, while animal models often do not accurately recapitulate specific disease phenotypes. These challenges impede research that may otherwise illuminate aspects of disease initiation and progression, leading to the ultimate identification of potential therapeutics. The establishment of induced pluripotent stem cells (iPSCs) as a human cellular model with defined genetics has provided the unique opportunity to study rare diseases within a controlled environment. iPSC models enable researchers to define mutational effects on specific cell types and signaling pathways within increasingly complex systems. Among rare diseases, pediatric diseases affecting neurodevelopment and neurological function highlight the critical need for iPSC-based disease modeling due to the inherent difficulty associated with collecting human neural tissue and the complexity of the mammalian nervous system. Rare neurodevelopmental disorders are therefore ideal candidates for utilization of iPSC-based in vitro studies. In this review, we address both the state of the iPSC field in the context of their utility and limitations for neurodevelopmental studies, as well as speculating about the future applications and unmet uses for iPSCs in rare diseases.