Astrocytes
Astrocytes perform multiple homeostatic functions in the CNS; they regulate the plasticity of synapses and synthesis of neurotransmitters (Ullian et al., 2004; Volterra and Meldolesi, 2005; Sloan and Barres, 2014), they maintain the blood brain barrier, and they provide neurotrophic support to MNs by releasing glial-derived neurotrophic factor (GDNF) and transforming growth factor β1 (TGF-β1) amongst others. Like microglia, during the neurodegenerative process, astrocytes can exist in two states, either reactive or activated, and activated astrocytes lose their neuroprotective functions and become neurotoxic during disease (Yamanaka et al., 2008; Ilieva et al., 2009; Valori et al., 2014; Das and Svendsen, 2015). Also, like microglia, astrocytes are implicated in the progression rather than onset of ALS. Deletion of SOD1 from astrocytes slowed disease progression, but not disease onset, in SOD1G93A mice (Yamanaka et al., 2008; Wang L. et al., 2011), whereas deletion of mutant SOD1 from MNs did delay onset (Boillée et al., 2006a; Wang L. et al., 2009). Furthermore, gene expression changes in MNs, astrocytes and oligodendrocytes start just before disease onset in SOD1G37R mice, but these alterations are first observed in MNs (Sun et al., 2015). Recently, two different subsets of reactive astrocytes were described in the adult CNS, A1 and A2 (Liddelow et al., 2017; Clarke et al., 2018; Miller, 2018) and the A1 reactive astrocytes were associated with the death of both neurons and oligodendrocytes (Liddelow et al., 2017).
There is increasing evidence that astrocytes mediate MN degeneration via the release of neurotoxic factors. Soluble toxic compounds produced by astrocytes expressing mutant SOD1 trigger the selective loss of spinal MNs (Nagai et al., 2007), but not spinal GABAergic neurons, consistent with the specific vulnerability of these cells in ALS (Nagai et al., 2007). Astrocytes in the ventral spinal cord can be distinguished from astrocytes in the dorsal spinal cord by expression of semaphorin A3 (Sema3a), which is implicated in the specific vulnerability to FF-MNs in ALS (see section “Neuroprotective and Neurotoxic Factor Expression in MN Subpopulations” below). Furthermore, astrocytes are also implicated in MN loss and disease progression by mediating AMPA receptor-induced excitotoxicity via EAAT2/GLT-1, as discussed below (section “Neuronal Excitability”). Expression of mutant TDP-43M337V in rat astrocytes led to down-regulation of neurotrophic genes, up-regulation of neurotoxic genes and progressive MN degeneration (Tong et al., 2013; Huang et al., 2014). Conditioned medium from primary astrocyte cultures of SOD1G86R and TDP-43A315T mice also induces MN death through activation of sodium channels and nitro-oxidative stress (Rojas et al., 2014). Furthermore, astrocytes expressing mutant FUSR521G trigger MN death by secreting pro-inflammatory tumor necrosis factor (TNF)-α (Kia et al., 2018). SOD1G93A aggregates in astrocytes appear in late disease stages, selectively in regions with extensive neuronal degeneration and prominent astrogliosis (Jaarsma et al., 2008). This raises the possibility that astroglial aggregate formation is triggered by MN degeneration, implying that disease may spread from neurons to glia (Jaarsma et al., 2008; Sun et al., 2015).
Together these studies suggest the involvement of astrocytes in the selective degeneration of MNs in ALS. Under normal conditions, astrocytes may be able to cope with the expression of low levels of misfolded proteins, but, during cell stress or in the context of MN degeneration, they become more vulnerable, and release factors toxic to MNs, thus producing a vicious cycle. However, the relative resistance of neuronal populations surrounded by reactive astrocytes indicates that the vulnerability of MNs is also determined by cell-autonomous components, such as their genetic background and transcriptional/translational profiles (Boillée et al., 2006a; Sun et al., 2015).