Oligodendrocytes and Schwann Cells
The two glial cell types responsible for myelination of axons have also been investigated in the context of ALS. Oligodendrocytes myelinate axons in the CNS whereas Schwann cells are responsible for myelination in the peripheral nervous system (PNS). Whilst they perform similar functions, there are also important differences between these two cell types. Schwann cells form a single myelin sheath around one single axon, whereas oligodendrocytes myelinate many different axons. Furthermore, there are differences in the protein composition of CNS and PNS myelin.
In ALS, TDP-43 pathology has been detected in oligodendrocytes in the motor cortex and spinal cord of both SALS and FALS patients (Arai et al., 2006; Mackenzie et al., 2007; Tan et al., 2007; Zhang et al., 2008; Seilhean et al., 2009; Murray et al., 2011; Philips et al., 2013). In addition, FUS forms cytoplasmic aggregates in oligodendrocytes from ALS patients bearing FUSR521C or FUSP525L mutations (Mackenzie et al., 2011). Degeneration of oligodendrocytes and their precursors was also linked with axon demyelination in both SALS and FALS patients (Kang et al., 2013). In SOD1G93A mice, oligodendrocyte loss in the spinal cord occurs before symptoms appear and importantly, before MN loss, implying that oligodendrocytes are associated with disease onset. This MN loss increases with disease progression, resulting in MNs with only partially myelinated axons in SOD1G93A mice and SOD1G93A rats (Niebroj-Dobosz et al., 2007; Kang et al., 2013; Philips et al., 2013). Whilst the proliferation of oligodendrocyte precursors may compensate for this loss, newly synthetized oligodendrocytes failed to mature and remain dysfunctional in SOD1G93A mice (Magnus et al., 2008; Philips et al., 2013). Recently, SOD1G85R was able to transfer from MNs to nearby oligodendrocytes (Thomas et al., 2017). The selective removal of mutant SOD1 from NG2+ oligodendrocyte progenitors, but not mature oligodendrocytes in SOD1G37R mice, leads to delayed disease onset and prolonged survival (Kang et al., 2013), further suggesting that mutant SOD1-induced oligodendrocyte defects are detrimental to MNs in ALS.
Schwann cells are required for the long-term maintenance of synapses at the NMJ (Reynolds and Woolf, 1992; Son and Thompson, 1995; Reddy et al., 2003). Early studies demonstrated that myelin is altered along peripheral nerves in ALS patients, implying that Schwann cells are involved in disease (Perrie et al., 1993). However, unlike the other glial cell types, more recent studies on the role of Schwann cells in ALS have reached conflicting conclusions. Knockdown of SOD1G37R within Schwann cells significantly accelerates disease progression, concomitant with a specific reduction in insulin-like growth factor (IGF-I), which is protective to MNs (see section “Neuroprotective and Neurotoxic Factor Expression in MN Subpopulations” below) (Lobsiger et al., 2009). This surprising finding, implying that SOD1G37R is protective in Schwann cells, could be linked to the dismutase activity of SOD1. Whereas SOD1G37R retains its enzymatic activity, SOD1G85R does not, and similar experiments performed in SOD1G85R mice resulted in opposite findings; Schwann cell specific knock-down of SOD1G85R delayed disease onset and extended survival (Wang et al., 2012). Furthermore, TGF-β1 produced by Schwann cells promotes synaptogenesis by increasing nerve-muscle contacts (Feng and Ko, 2008), in contrast to TGF-β1 expression in astrocytes which accelerates disease progression in SOD1 mice (Endo et al., 2015). Hence, the role of Schwann cells in ALS remains unclear.