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.

Keywords: Aicardi-Goutières syndrome; astrocytes; interferon; type I interferonopathy.

Figure 1

Molecular pathways and activation of innate immune signaling pathway in AGS. 1 In AGS individuals, the mutated form of TREX1 loses its ability to inhibit expression of the protein ORF1P which is essential for assembly of the retro element L1 and hence mutant TREX1 cannot block the L1 activity. Additionally, altered TREX1 loses 3′ exonuclease activity and fails to degrade products of reverse transcriptase single‐stranded (ss) and double‐stranded (ds) DNA, which starts accumulating and stimulates the innate immune system via cGAS‐STING pathway. This leads to serine‐threonine protein kinase (TBK1) mediated phosphorylation of IFN regulator 3 (IRF3) triggering Interferon stimulated genes (ISGs) to produce IFN‐α. Targeting reverse transcriptase could be a good therapeutic target for TREX1 AGS individuals. 2 RNASEH2, a complex of RNASEH2A, RNASEH2B and RNASEH2C degrades RNA : DNA hybrid. However, in AGS individuals, the exact mechanism of how it induces IFN‐α stimulation is unknown. Rnaseh2b deficient cells accumulate damaged cytosolic DNA aggregates in form of micronuclei. These micronuclei stimulate expression of ISGs via binding to cGAS. This mechanism could be operating in AGS individuals as it is believed that there is presence of endogenous damaged DNA molecules. Additionally, micronuclei associated with Rnaseh2b deficiency were cleared by induction of autophagy through pharmacological inhibition of the mechanistic target of rapamycin (mTOR) pathway and could be a feasible therapeutic option for RNASEH2B‐dependent disease. 3 In SAMHD1 AGS individuals, a likely source of endogenous nucleic acid could be due to failure to regulate L1 retro transposition. Moreover, mutated SAMHD1 cannot clear the dNTPs and ssRNA resulting in activation of IFN‐α via cGAS‐STING pathway. 4 In ADAR1 mutants, there is an accumulation of dsRNA and this dsRNA binds to MDA5/IFIH1 and activates the MAVS pathway further triggering IFN‐α production. In addition, the anti‐viral pathways PKR and OAS‐RNAse L system are also activated in the absence of ADAR1 editing. 5 MDA5/IFIH1 mutation is another gene in AGS individuals which causes increase of IFN‐α production by MAVS pathway. Targeting of the downstream signaling MDA5/MAVS pathway could also be a promising therapeutic option in AGS individuals with ADAR1 and MDA5 mutation.

Figure 2

Peripheral and CNS cellular contributions toward IFN signature and its downstream effects in AGS. 1 The presence of AGS mutation causes abnormal accumulation of nucleic acids, which leads to activation of the cGAS‐STING and MDA‐MAVS pathway in the innate immune cells–dendritic cells and macrophages. They mount an inflammatory response through release of interferon alpha (IFN‐α), activation of IFN stimulated genes (ISG) and induction of other cytokines. 2 These innate immune cells further activate the adaptive immune monocytes, triggering the T and B cells to release inflammatory molecules and auto‐antibodies, respectively. 3 The peripheral IFN‐α signature causes microangiopathy and AGS mutations affect the health of endothelial cell through release of pro‐inflammatory cytokines and deposition of calcifications. 4 A clinical diagnostic marker for AGS is increased CSF IFN‐α and lymphocytosis, with supporting evidence of infiltrating T cells observed in post‐mortem brains from AGS individuals. 5 This peripheral IFN signature impinges on the underlying BBB and the adjoining astrocyte end feet, potentially contributing to astrogliosis. 6 The astrocytes harboring the AGS mutation have a cell autonomous effect leading to astrogliosis along with release of IFN‐α and stimulating production of ISGs. 7 Astrocytes with AGS mutations, particularly TREX1 mutations, have altered survival eventually leading to cell death. 8 Along with the cell‐autonomous effect of neurons on themselves, astrocyte mediated release of IFN signature can in turn exert a non‐cell autonomous effect resulting in neuronal toxicity and death. 9 While it is not tested yet, harboring AGS mutations could potentially activate microglia directly in a cell‐autonomous fashion or through release of IFN signature from astrocytes causing reactive microgliosis, which can further propagate non‐cell autonomous effects. 10 Similarly, the contribution of oligodendrocytes in AGS is not explored and could potentially worsen the ongoing pathology in the CNS due to loss of oligodendrocytes and myelinated axons.