Astrocytes, an active player in Aicardi–Goutières syndrome

Abstract

Aicardi-Goutières syndrome (AGS) is an early-onset, autoimmune and genetically heterogeneous disorder with severe neurologic injury. Molecular studies have established that autosomal recessive mutations in one of the following genes are causative: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1/MDA5. The phenotypic presentation and pathophysiology of AGS is associated with over-production of the cytokine Interferon-alpha (IFN-α) and its downstream signaling, characterized as type I interferonopathy. Astrocytes are one of the major source of IFN in the central nervous system (CNS) and it is proposed that they could be key players in AGS pathology. Astrocytes are the most ubiquitous glial cell in the CNS and perform a number of crucial and complex functions ranging from formation of blood-brain barrier, maintaining ionic homeostasis, metabolic support to synapse formation and elimination in healthy CNS. Involvement of astrocytic dysfunction in neurological diseases-Alexander's disease, Epilepsy, Alzheimer's and amyotrophic lateral sclerosis (ALS)-has been well-established. It is now known that compromised astrocytic function can contribute to CNS abnormalities and severe neurodegeneration, nevertheless, its contribution in AGS is unclear. The current review discusses known molecular and cellular pathways for AGS mutations and how it stimulates IFN-α signaling. We shed light on how astrocytes might be key players in the phenotypic presentations of AGS and emphasize the cell-autonomous and non-cell-autonomous role of astrocytes. Understanding the contribution of astrocytes will help reveal mechanisms underlying interferonopathy and develop targeted astrocyte specific therapeutic treatments in AGS.

A phenolic small molecule inhibitor of RNase L prevents cell death from ADAR1 deficiency

“…Thus, we tested VAL in an A549 ADAR1-knockout or -knockdown cellular background and observed that VAL selectively inhibited RNase L to suppress cell death. By demonstrating that inhibiting RNase L ribonuclease activity can attenuate ADAR1-associated apoptosis, these results indicate that RNase L is a viable therapeutic target in the context of select cases of AGS with ADAR1 mutations (53). Furthermore, because VAL inhibits RNase L, it is reasonable to expect that, during viral infections, VAL treatment will result in fewer RNA cleavage products to stimulate RIG-I/MDA5 and NLRP3 (25,54).…”

Genetic diagnosis of neonatal-onset seizures

“…In this study, no febrile-related seizures were noted. Hence phenotypic diversity needs to be considered 18, 19, 20, 21. It is worth noting that one of the children with the nodular sclerosis-related gene TSC2 had no seizures after discharge and no signs of nodular sclerosis.…”

Astrocyte–Oligodendrocyte–Microglia Crosstalk in Astrocytopathies

“…Four additional genes have been added to the list of AGS causative genes, including RNASEH2C, SAMHD1, ADAR1, and IFIH1/MDA5 (Livingston et al, 2013). Sase et al (2018) overviewed the cellular pathways leading to the AGS phenotype and concluded that the underlying pathophysiological mechanism concerns increased production and dysregulated control of IFNα levels by activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway (Sase et al, 2018). As astrocytes are a major source of IFNα production, this condition is now considered an astrocytopathy (van der Knaap and Bugiani, 2017).…”