Astroglial transcriptome dysregulation in early disease of an ALS mutant SOD1 mouse model

Abstract

Astroglia are a morphologically diverse and highly abundant cell type in the CNS. Despite these obvious observations, astroglia still remain largely uncharacterized at the cellular and molecular level. In disease contexts such as amyotrophic lateral sclerosis (ALS), it has been widely shown that astroglia downregulate crucial physiological functions, become hypertrophied, reactive, and toxic to motor neurons. However, little is known about the astroglia-specific transcriptomic changes that occur during ALS disease progression, especially early in disease. To address this, we FACS-isolated pure astroglia from early and mid-symptomatic superoxide dismutase 1 (SOD1) G93A spinal cord and performed microarray sequencing, in hopes to uncover markers and pathways driving astroglia dysfunction in ALS. After extensive analyses, we uncovered genes selectively enriched and downregulated in both control and SOD1 astroglia at both disease points. In addition, we were able to identify genes and pathways differentially expressed that may have relevance with other neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, suggesting a common theme among astroglial dysfunction in neurodegenerative disease. In aggregate, this study sheds light on the common and unique themes of dysfunction that astroglia undergo during neurodegenerative disease progression and provides candidate targets for therapeutic approaches.

Astrocyte Heterogeneity in the Adult Central Nervous System

“…This same subpopulation of astroglia also downregulate Kir4.1, which could serve to exacerbate these hyperexcitable deficits (Kaiser et al, 2006 ). Transcriptomic data shows that astroglia in an ALS mouse model alter greatly their transcriptome during disease progression (Miller et al, 2017 ). In in vitro models of ALS, human and rodent astroglia release neurotoxic factors to motor neurons, rendering them susceptible to degeneration (Figure 1 , Table 1 , Supplementary Table S1 , Phatnani et al, 2013 ).…”

“…However, the functionality of these cell types is highly diverse and dependent on countless factors, including their neuroanatomical localization (Krencik et al, 2011 ). Over the past several decades, researchers have identified a high degree of diversity within each of these cell types, and they have also learned much about how functions of these cell types are altered during disease pathogenesis (Miller et al, 2017 ). However, there still remain major gaps in our understanding about the identification and overall characterization of different astroglia populations.…”

Cortical astroglia undergo transcriptomic dysregulation in the G93A SOD1 ALS mouse model

“…Astroglia in different anatomical regions exhibit highly different molecular profiles. Importantly, these molecular profiles also have been shown to change dramatically in neurological disease (Miller, Zhang, Glatzer, & Rothstein, 2016). In motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), astroglia downregulate essential ion and neurotransmitter transporters such as the synaptically-localized glutamate-transporter I, Glt1, and potassium ion channel, Kcnj10 (Kaiser et al, 2006; Rothstein, Van Kammen, Levey, Martin, & Kuncl, 1995).…”

Rising Stars: Astrocytes as a Therapeutic Target for ALS Disease

“…Then, upon disease onset and appearance of motor deficiency symptoms, probably after damage to the MN or astrocytes crosses metabolic threshold, the astrocytes acquire the A1 phenotype with neurotoxic properties. Transcriptomic data shows that astroglia in late stage of disease progression in ALS mouse model acquire A1-reactive astrocytic phenotype (Miller et al, 2017). In ALS patients' reactive astrocytes are observed in susceptible areas and the level of reactivity correlates with the neurodegeneration stage of ALS patients.…”