Inhibition of NF-κB in astrocytes is sufficient to delay neurodegeneration induced by proteotoxicity in neurons

Abstract

BackgroundMost neurodegenerative diseases associated with protein aggregation are hallmarked by activation of astrocytes. However, how astrocytes are activated or which signaling pathways in astrocytes contribute to pathogenesis is not clear. One long-standing question is whether the responses in astrocytes are due to stress or damage in astrocytes themselves, or because of astrocytic responses to cellular stress or damage in neurons. Here, we examine responses in astrocytes induced by expression of disease-associated, aggregation-prone proteins in other cells. We also examine the consequences of these responses in astrocytes in a model for neurodegeneration.MethodsWe first examined a role for intracellular astrocytic responses in a Drosophila model for Spinocerebellar ataxia type 3 (SCA3, also known as Machado–Joseph disease), a disease caused by expansion of the polyglutamine (polyQ) stretch in the ATXN3 gene. In this Drosophila SCA3 model, eye-specific expression of a biologically relevant portion of the ATXN3 gene, containing expanded polyQ repeats (SCA3polyQ78) was expressed. In a candidate RNAi screen in the Drosophila SCA3 model, we analyzed whether downregulation of expression of specific genes in astrocytes affected degeneration induced by SCA3polyQ78 expression in Drosophila eyes. We next examined the role of astrocytes in response to proteotoxic stress in neurons induced by SCA3polyQ78 expression or amyloid beta peptides, associated with Alzheimer’s disease.ResultsEye-specific expression of SCA3polyQ78 resulted in the presence of astrocytes in the eye, suggesting putative involvement of astrocytes in SCA3. In a candidate RNAi screen, we identified genes in astrocytes that can enhance or suppress SCA3polyQ78-induced eye degeneration. Relish, a conserved NF-κB transcription factor, was identified as an enhancer of degeneration. Activity of Relish was upregulated in our SCA3 model. Relish can exert its effect via Relish-specific AMPs, since downregulation of these AMPs attenuated degeneration. We next examined Relish signaling in astrocytes on neurodegeneration. Selective inhibition of Relish expression specifically in astrocytes extended lifespan of flies that expressed SCA3polyQ78 exclusively in neurons. Inhibition of Relish signaling in astrocytes also extended lifespan in a Drosophila model for Alzheimer’s disease.ConclusionsOur data demonstrate that astrocytes respond to proteotoxic stress in neurons, and that these astrocytic responses are important contributors to neurodegeneration. Furthermore, our data demonstrate that activation of NF-κB transcription factor Relish in astrocytes, induced by proteotoxic stress in neurons, enhances neurodegeneration, and that specific Relish inhibition in astrocytes extends lifespan. Our data provide direct evidence for cell-non-autonomous contributions of astrocytes to neurodegeneration, with possible implications for therapeutic interventions in multiple neurodegenerative diseases.Electronic supplementary materialThe online version of this article (10.1186/s1297...

Drosophila Glia: Models for Human Neurodevelopmental and Neurodegenerative Disorders

“…It has been shown that specific Relish inhibition in astrocytes delays neurodegeneration and extends lifespan. These data provide further evidence for the non-cell-autonomous contributions of astrocytes to neurodegeneration, albeit from an opposing perspective [161].…”

Antisense oligonucleotide therapy rescues aggresome formation in a novel Spinocerebellar Ataxia type 3 human embryonic stem cell line

“…In addition, SCA3 research to date has been neuron-centric, meaning that little is known about glial involvement in disease progression. Recent studies demonstrating significant transcriptional and protein expression changes in glial-enriched genes [62][63][64] and altered glial morphology and density in affected brain regions with disease progression 4,65 point to the need for glial-focused investigations in SCA3. The pluripotent potential of SCA3-hESC in combination with the detection of native mutATXN3 aggregation demonstrated here, could prove invaluable for future studies of cell-type specific differences in ATXN3 function, aggregation propensity and vulnerability to aggregation-induced cellular insults.…”

Short and long TNF‐alpha exposure recapitulates canonical astrogliosis events in human‐induced pluripotent stem cells‐derived astrocytes

“…First, we aimed to determine whether human iPSC‐derived astrocytes were responsive to TNF‐α by analyzing nuclear translocation of the transcription regulator NF‐kB p65 subunit, a mandatory step on NF‐kB‐mediated gene expression regulation and astrogliosis induction (Brambilla et al, ; Li, Sibon, & Dijkers, ; Saggu et al, ). It can be noted that cells incubated for 1 hr with TNF‐α ranging from 1 to 50 ng/ml showed nuclear translocation of NF‐kB in all tested conditions (Figure 2a).…”