Neuronal cytoplasmic inclusions have been extensively described in ALS and FTD, but many studies have also reported the presence of inclusions in oligodendrocytes, as well as other glial cells. In general, these oligodendroglial inclusions mainly appear in the ventral horns of the spinal cord, corticospinal tracts and frontal cortex, which are the most affected areas in ALS or FTD, and they are essentially found around the nucleus and periaxonal cytoplasm (Stieber et al., 2000; Fatima et al., 2015; Ferraiuolo et al., 2016; Tables 1, 2).

Whether oligodendrocytes degenerate in ALS and FTD is a matter of controversy. IPSC-derived oligodendrocytes obtained from sporadic and familial ALS patients did not display any sign of degeneration, suggesting that their death, if it occurs, may depend on the disease cellular environment (Ferraiuolo et al., 2016). In fact, gray matter oligodendrocytes in the ventral spinal cord of SOD1^G93A mice and zebrafish did express markers of apoptosis (Philips et al., 2013; Kim et al., 2019). In addition, the death of these cells started before the onset of overt disease, with only less than half of the oligodendrocytes produced during the first post-natal months surviving by the end stage, causing a decrease in the absolute number of mature oligodendrocytes in both gray and white matter (Kang et al., 2013; Bonfanti et al., 2020). Similarly, the specific deletion of Tardbp in mouse oligodendrocytes (oligo-Tardbp-KO mice) reduced the number of gray matter oligodendrocytes that reach the symptomatic stage, although it did not affect white matter oligodendrocytes (Ho et al., 2021). Oligodendroglial degeneration also occurred in Tardbp^WT mice, as deduced from the localization of the pro-apoptotic factor caspase-3 in cells positive for the oligodendrocyte marker adenomatous polyposis coli (Yang et al., 2022).

It has also been postulated that the proliferation and differentiation of OPCs could compensate for the loss of mature oligodendrocytes (Philips et al., 2013; Cui et al., 2014). In support of this notion, loss of cells positive for oligodendrocyte transcription factor 2 (OLIG2) that was observed in the corpus callosum of a FTD mouse model lacking the gene encoding the lysosomal transmembrane protein 106B (TMEM106B), affected differentiated but not undifferentiated oligodendrocytes. It was proposed that these undifferentiated cells represented a population of reactive precursors trying to replace the lost oligodendrocytes (Zhou et al., 2020). Perhaps more surprisingly, the number of mature oligodendrocytes was unaltered when knocking out Fus specifically in mouse oligodendrocytes (oligo-Fus-KO mice) (Guzman et al., 2020), and Fus^ΔNLS mice even showed an increase in the number of white matter oligodendrocytes in the ventral horns of the spinal cord (Scekic-Zahirovic et al., 2017). Therefore, based on the amounts of mature oligodendrocytes, it appears that the population of oligodendroglial cells is affected by the lack of FUS and/or delocalization of its truncated form in a manner different from that observed in models having other disease-linked gene alterations.

Diffuse myelin pallor, spongiosis and demyelination were observed in the spinal cord, brainstem, motor cortex and subcortical white matter of patients with sporadic and familial ALS (Hayashi et al., 2001; Kang et al., 2013; Nolan et al., 2021). Of note, the gray matter was more affected in the motor cortex than in the ventral spinal cord (Kang et al., 2013). In contrast, these findings were not confirmed in Tardbp^WT mice since demyelination rather appeared in the white matter, mainly in the lumbar spinal cord, and became less severe toward the rostral areas of the brain (Yang et al., 2022). These observations emphasize, once again, the differences between white and gray matter as well as between cortical and spinal cord involvement. It should be mentioned, however, that other studies did not corroborate these findings. Spectral confocal reflectance imaging of samples from sporadic and familial ALS cases showed a normal compact myelin and no changes in myelin density in at least the motor cortex white matter (Sadler et al., 2022).

The main myelin alteration in the motor cortex of ALS patients was the presence of water, both inside and outside the myelin sheath (Kolind et al., 2013). A similar alteration was observed in the spinal cord of SOD1^G93A mice and rats even at a pre-symptomatic stage, accompanied by the vacuolization and detachment of myelin lamellae eventually leading to the loss of compaction and destruction of the myelin sheath, and to the accumulation of myelin debris around degenerating axons suggestive of Wallerian degeneration. Moreover, the severity of these modifications increased as the disease progressed (Niebroj-Dobosz et al., 2007; Kang et al., 2013). The myelin sheath in the gray matter of the ventral spinal cord of SOD1^G93A and Fus^ΔNLS mice also exhibited a lower ratio of the inner-to-outer diameter of myelinated axons (also referred to as the g-ratio), suggesting an abnormally thick myelin sheath and potential disturbances to axon function (Kang et al., 2013; Scekic-Zahirovic et al., 2017).

High levels of cholesterol esters were detected in the white matter of the cortex and spinal cord of sporadic ALS patients, with this increase also correlating to a shorter disease duration (Cutler et al., 2002; Sadler et al., 2022). This alteration was also observed in the spinal cord of SOD1^G93A mice (Chaves-Filho et al., 2019). Similarly, an accumulation of cholesterol esters was found in the frontal and parietal white matter of FTD patients carrying a progranulin mutation, although it was not observed in C9orf72 repeat expansion carriers. Since excess cholesterol typically accumulates in the form of esters, the increased amounts of these lipids could result from myelin breakdown (Marian et al., 2023). In contrast to these findings, oligo-Fus-KO mice showed an increase in cholesterol in the corpus callosum, associated with an increase in the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme for cholesterol synthesis, which suggests the formation rather than destruction of myelin. In accordance with this hypothesis, these mice exhibited a decreased g-ratio, indicating thicker myelin sheaths (Guzman et al., 2020).

Low levels of sphingomyelin and ceramides were found in the cortical white matter of patients with sporadic and familial ALS (Sadler et al., 2022). Conversely, significant amounts of these lipids were detected in the cerebrospinal fluid, suggesting a progressive destruction of the myelin sheath (Blasco et al., 2017). A decreased content of sphingolipids was also observed in the hippocampus of FTD patients carrying the risk allele of TMEM106B (Lee et al., 2023), as well as in the frontal cortex white matter of FTD patients carrying the progranulin or C9orf72 repeat expansion mutation (Marian et al., 2023). In contrast, levels of sphingomyelin were increased in the spinal cord white matter of ALS patients, and in pre-symptomatic and symptomatic SOD1^G93A mice (Cutler et al., 2002), highlighting clear-cut differences in terms of lipid alterations in different areas of the CNS.

The studies investigating the protein composition of myelin in ALS and FTD reported contrasting changes at the mRNA and protein level. An integrative transcriptomic analysis of post-mortem spinal cord samples from ALS and ALS/FTD patients revealed a down-regulation of the expression of several genes that were specifically ascribed to the oligodendrocyte cell type; in particular, a decrease in the expression of MOBP, involved in myelin compaction, was observed (Humphrey et al., 2023). The expression of Mbp, Mag, Mog, and Cnp was also decreased in end stage oligo-Tardbp-KO mice, along with HMGCR in patients with TDP43 proteinopathy (Ho et al., 2021). Additional genes, characteristic of peripheral myelin, such as myocilin, Pmp2 and Prx, were also down-regulated in the spinal cord of Fus^ΔNLS mice (Scekic-Zahirovic et al., 2017). On the other hand, symptomatic oligo-Fus-KO mice showed an increase in the expression of Hmgcr but no changes in other major myelin genes were detected (Guzman et al., 2020).

The alterations in gene expression mentioned above did not always correlate with changes in protein content, suggesting different mechanisms of dysregulation at transcriptional, translational and/or post-translational level. MBP content was reduced in the gray matter of the motor cortex and spinal cord of patients with sporadic and familial ALS, specifically carrying a SOD1 or C9orf72 repeat expansion mutation (Kang et al., 2013; Rohan et al., 2014). This was not observed in the cortical white matter of sporadic or familial ALS cases (Sadler et al., 2022), consistent with the general trend that gray matter seems to be more affected than white matter. Decreased MBP levels were also found in the white and gray matter of the frontal cortex of FTD patients carrying a progranulin or C9orf72 repeat expansion mutation but not in sporadic cases (Lorente Pons et al., 2020; Sirisi et al., 2022; Marian et al., 2023). The decrease in MBP was associated with a reduction in the contents of other major myelin proteins, including CNP and PLP, in FTD patients carrying a progranulin (but not C9orf72 repeat expansion) mutation, as well as in ALS patients carrying a TARDBP mutation (Kang et al., 2013; Marian et al., 2023). Finally, MBP levels were decreased in Tardbp^WT mice (Yang et al., 2022) but unaffected in SOD1^G93A rats (Niebroj-Dobosz et al., 2007).

Several studies have interrogated whether oligodendrocytes are affected by ALS and FTD in a cell-autonomous manner. Abnormal aggregates are well known to perturb numerous cellular functions, and this can be especially relevant for oligodendrocytes in which the accumulation of certain pathogenic factors is particularly enhanced, as compared to other cell types. Thus, the expression of C9orf72, which is normally high in oligodendrocytes, was increased specifically in regions affected by ALS, hence favoring the toxic accumulation of expanded C9orf72 RNA repeats particularly in oligodendrocytes (Langseth et al., 2017). In contrast, mature oligodendrocytes contained less misfolded SOD1 inclusions than other cell types (Forsberg et al., 2011), possibly due to the fact that oligodendrocytes highly express the heat shock protein αB-crystallin, which prevents the conversion of soluble SOD1 into insoluble forms prone to aggregate (Wang et al., 2005). Despite such a protective mechanism, SOD1 still accumulated in oligodendrocytes of SOD1^G93A zebrafish associated with fluid vacuoles located between decompacted myelin lamellae (Kim et al., 2019). These vacuoles also appeared in oligo-Tardbp-KO mice, combined with a decrease in myelin sheath thickness and the down-regulated expression of several major myelin genes, including Mbp, Plp, Mog, and Mag, which resulted in a concomitant reduction in the content of at least MBP and MOG. Interestingly, these alterations occurred in the gray and white matter of the spinal cord even in the absence of motor neuron cell death and were sufficient to trigger a progressive decrease in muscle strength and motor coordination together with a shortened lifespan (Wang et al., 2018). Another mouse model of ALS obtained by knocking out optineurin in mature oligodendrocytes also exhibited abnormal myelination in the ventrolateral white matter of the spinal cord (Ito et al., 2016). Likewise, oligo-Fus-KO and Fus^ΔNLS mice showed FTD-like behavioral alterations, mainly hyperactivity and disinhibition, which correlated with an increase in myelin thickness without signs of neuronal death (Scekic-Zahirovic et al., 2017, 2021; Guzman et al., 2020). Taken together, these findings point to cell-autonomous alterations occurring specifically in oligodendrocytes that very likely contribute to the whole disease picture.

Several mechanisms have been postulated to explain the degeneration of mature oligodendrocytes in ALS and FTD (Ito et al., 2009; Iuchi et al., 2021). Firstly, oligodendrocytes can die due to the loss of function of key proteins necessary for their survival that frequently appear trapped in the cytoplasmic inclusions characteristically seen in these conditions. Deleting Tardbp expression in cultured oligodendrocytes triggered cell death through the activation of a necroptosis mechanism mediated by receptor-interacting protein kinase 1, which highlights the essential role of TDP43 in oligodendrocyte survival (Wang et al., 2018; Ho et al., 2021). Strikingly, deleting Tardbp expression in vivo specifically in astrocytes also triggered a selective reduction in the number of mature oligodendrocytes, and it was suggested that the loss of TDP43 could contribute to kill oligodendrocytes (and neurons) by modifying the gene expression program of astrocytes toward a pro-inflammatory phenotype (Peng et al., 2020).

Mature oligodendrocytes are sensitive to glutamate excitotoxicity and, like neurons, they can die from excessive glutamate exposure (Xu et al., 2008). Normally, OPCs express Ca²⁺-permeable AMPA receptors that become impermeable upon differentiation to mature oligodendrocytes. This transition was impaired in oligodendrocytes from ALS patients carrying a Tardbp mutation, rendering AMPA receptors still permeable to Ca²⁺ and enhancing vulnerability to excitotoxicity (Barton et al., 2021). Under physiological conditions, free fatty acids, such as oleic acid and linoleic acid, help to inhibit glutamate-induced cell death. The levels of oleic acid and linoleic acid stayed low in the plasma of SOD1^G93A mice prior to disease onset, which could be related to a higher vulnerability to excitotoxicity. In fact, feeding SOD1^G93A mice with a cocktail rich in oleic acid and linoleic acid suppressed oligodendrocyte cell death in the spinal cord of these mice, further reinforcing the link between glutamate excitotoxicity and mature oligodendrocyte degeneration (Maruyama et al., 2023).

Finally, not all the alterations affecting proteins essential for maintaining the activity of oligodendrocytes triggered their degeneration. The decreased expression of the monocarboxylate transporter MCT1 observed in sporadic ALS patients and SOD1^G93A mice was implicated in affecting the metabolic support of axons by oligodendrocytes, causing axonal damage and neuronal loss. However, such a decrease in MCT1 expression did not cause any death of cultured oligodendrocytes, and oligodendrocytes from heterozygous MCT1 null mice did not show any change in morphology and number (Lee et al., 2012).

Several mechanisms have been proposed to contribute to the impairment of OPC differentiation seen in ALS and FTD. Under physiological conditions, the expression of G protein-coupled receptor 17 (GPR17) is normally down-regulated to enable the differentiation of OPCs. Increasing the expression of this receptor is enough to block the maturation process (Fumagalli et al., 2015). GPR17 levels appeared increased in the spinal cord of SOD1^G93A mice even at a pre-symptomatic stage. In addition, the percentage of mature cells derived from cultured OPCs obtained from SOD1^G93A mice was increased by blocking GPR17. Overall, these findings suggest a role for GPR17 in ALS (Bonfanti et al., 2020). Erb-B2 receptor tyrosine kinase 4 (ERBB4) is known to play an important role in oligodendrocyte maturation and is also involved in myelin formation. Interestingly, several mutations in ERBB4 were identified as causing late-onset ALS, and the expression of ERBB4 was decreased in the spinal cord of sporadic cases (Takahashi et al., 2019). Since ERBB4 expression is in part controlled by interacting with TDP43, it was postulated that the cytoplasmic delocalization of TDP43, typically observed in ALS and FTD, could affect ERBB4 mRNA transport and/or translation and hence impair oligodendrocyte maturation (Schwenk et al., 2016). Von Hippel Lindau protein (VHL) is another key player in OPC differentiation and myelination (Yuen et al., 2014), shown to colocalize with phosphorylated TDP43 in cytoplasmic inclusions of OPCs and oligodendrocytes in the spinal cord of sporadic ALS patients. This interaction was more defined in these cells than in any other cell type and was promoted in the presence of misfolded TDP43. In fact, VHL and TDP43 stabilized and enhanced the formation of perinuclear inclusions of each other, thus preventing their degradation. A similar mechanism was found to occur with mutant SOD1. It was proposed that the aggregates of phosphorylated TDP43 stimulate the accumulation of VHL in insoluble fractions, and hence limits OPC differentiation and myelination (Uchida et al., 2016). Finally, notch receptor 1 (NOTCH1) is an important negative regulator of OPC differentiation, and its expression was decreased in ALS patients and SOD1^G93A mice (Zhang et al., 2009). However, follow-up studies did not corroborate these findings (Liu et al., 2020), and the conditional deletion of Notch1 in OPCs failed to improve oligodendroglial function and disease outcome in SOD1^G93A mice (Eykens et al., 2018).

Oxidative stress has been shown to play a crucial role in ALS and FTD (Motataianu et al., 2022). Regarding oligodendrocytes, oxidative stress impaired the maturation of OPCs not only by decreasing the expression of genes promoting their differentiation, such as SRY-box transcription factor 10 and OLIG2, but also by increasing the expression of genes known to inhibit it, such as the family of inhibitors of DNA binding and cell differentiation (Id) genes. Oxidative stress also affected the deacetylation of histones necessary to initiate OPC differentiation (French et al., 2009). Lastly, since the process of differentiation into mature oligodendrocytes can be interrupted through the activation of a toll-like receptor 3-dependent pathway, it was postulated that the implication of pro-inflammatory mechanisms, commonly observed in ALS and FTD, could alter, at least in part, OPC differentiation (Boccazzi et al., 2021).

Besides the loss of mature oligodendrocytes and the impairment in OPC maturation, the formation and maintenance of the myelin sheath can also be affected in ALS and FTD (Figure 1). In agreement with this notion, the reduction in the content of MBP in the spinal cord of ALS and FTD patients with TDP43 proteinopathy did not correlate with the decrease in the number of mature oligodendrocytes, which strongly suggests that certain myelin modifications can take place, at least in part, as an independent event (Rohan et al., 2014). The fact that myelin defects were observed around uninjured axons in SOD1^G93A mice also suggests that the alterations of the myelin sheath may occur prior to motor neuron loss (Kang et al., 2013). Several mechanisms have been proposed to explain the modifications of the myelin sheath observed in ALS and FTD.

Several genes whose mutations have been linked to ALS and/or FTD, such as TARDBP, FUS, angiogenin and HNRNP1, are normally implicated in different aspects of the metabolism of RNA. For example, TDP43 is known to bind to mRNAs encoding major myelin proteins, including MBP, PLP, MOG and MAG. Not surprisingly, these mRNAs were progressively down-regulated in the spinal cord of oligo-Tardbp-KO mice (Wang et al., 2018). Similarly, FUS was shown to bind to Mbp mRNA, and knocking out Fus produced aberrant splice variants of Mobp and Mag RNA (Hoell et al., 2011; Lagier-Tourenne et al., 2012). Overall, these findings point to an equilibrium between myelin RNAs and associated RNA binding proteins necessary to ensure proper myelination. Particularly for MBP mRNA, binding to HNRNPA2 is required for transport to the myelin sheath, where it is then translated. Interestingly, mutant forms of ALS and FTD-linked TDP43 and C9orf72 were shown to trap HNRNPA2, likely compromising the transport of Mbp mRNA toward the myelin sheath (Buratti et al., 2005; DeJesus-Hernandez et al., 2011; Lorente Pons et al., 2020). Consistent with these findings, the trafficking of MBP mRNA was altered in ALS patients carrying a C9orf72 repeat expansion mutation, although this alteration did not cause any noticeable modification in the general structure of myelin (Barton et al., 2021). In oligodendrocytes, as in neurons, microtubule dynamics and stabilization are essential not only to allow the formation of cellular processes and myelin extensions but also to assure mRNA transport. The microtubule-associated protein Tau, which appears frequently aggregated in cases of FTD, is involved in these processes. Thus, the oligodendroglial knock-down of Mapt, the gene encoding Tau protein, triggered the retention of Mbp mRNA in the cell soma, causing a decrease in peripheral Mbp expression and subsequent impaired myelination (Carson et al., 1997; Seiberlich et al., 2015). Finally, the analysis of the brain transcriptome in a mouse model of FTD lacking TMEM106B showed a generalized down-regulation of genes implicated in myelination and axonal ensheathment. This was associated with the delocalization of the myelin protein PLP1 in lysosomes instead of being properly assembled into the membrane sheath, indicating the importance of TMEM106B for PLP1 transport (Zhou et al., 2020).

Cholesterol is the most present lipid component of the myelin sheath. Under physiological conditions, TDP43 binds to the mRNAs encoding HMGCR and sterol regulatory element binding transcription factor 2 (SREBF2) and promotes the expression of these genes involved in cholesterol synthesis. The expression of HMGCR was reduced in oligodendrocytes of FTD patients with TDP43 proteinopathy, and that of Srebf2 was also decreased in oligo-Tardbp-KO mice. However, re-expressing Srebf2 in these mice restored cholesterol levels and protected against the demyelination caused by the lack of TDP43 (Ho et al., 2021). Many genes implicated in cholesterol metabolism also display binding motifs for FUS but, in contrast to what was observed with TDP43, the expression of Hmgcr was rather increased in oligo-Fus-KO mice concomitantly with an increase in cholesterol content and myelin thickness (Guzman et al., 2020). Oligodendrocytes need large amounts of cholesterol for the formation and maintenance of the myelin sheath. The import of cholesterol from astrocytes mediated by low-density lipoprotein receptor (LDLR) is one of the mechanisms making cholesterol available to oligodendrocytes. TDP43 co-aggregated with LDLR in oligodendrocytes of FTD patients with TDP43 proteinopathy, and the expression of LDLR itself was decreased in oligo-Tardbp-KO mice, suggesting a reduction in the transfer of cholesterol and a defect of myelination. Consistent with these findings, supplementing cultured oligodendrocytes of oligo-Tardbp-KO mice with cholesterol restored their myelinating capacity lost in the absence of TDP43 (Ho et al., 2021). Astrocytes also provide oligodendrocytes with lactate, via MCT1, and lactate is then used to synthesize different classes of myelin lipids (Rinholm et al., 2011). The generalized reduction in MCT1 levels observed in the CNS of ALS patients and related animal models could therefore result in deficient intake of lactate by oligodendrocytes and subsequent impaired myelination.

Sphingolipids are also important constituents of the myelin sheath. The presence of the disease risk allele of TMEM106B was associated with reduced levels of myelin sphingolipids in the hippocampus of patients with FTD (Lee et al., 2023). Similarly, a loss of myelin sphingolipids was found in FTD patients carrying a progranulin mutation, and a mouse model of FTD lacking progranulin showed changes in the activity of enzymes involved in sphingolipid metabolism, which strongly suggests the implication of such genes in maintaining oligodendroglial function (Huang et al., 2020; Lok and Kwok, 2021).

It has been observed in several neurodegenerative diseases that the structure and function of certain proteins may be affected by post-translational citrullination. Levels of citrullinated proteins, as well as those of the peptidylarginine deiminases responsible for citrullination, were increased in the spinal cord of mice carrying an ALS-linked SOD1^G93A or profilin mutation. Interestingly, these citrullinated proteins formed aggregates containing MBP and PLP. In fact, the citrullination of MBP caused its dissociation from the membrane, and dissociated MBP formed extended structures prone to aggregate or be proteolyzed. It was hypothesized that the proteolysis of such structures could release immunogenic peptides, eventually triggering a kind of autoimmune response and the subsequent destruction of the myelin sheath (Yusuf et al., 2022). Of note, myelin phagocytosis could be also caused by macrophages stimulated in response to abnormally high levels of glycine, as deduced from an increase in glycine content found in the plasma of ALS patients (Carmans et al., 2010).

Given the intimate connection with axons, it seems very likely that oligodendrocytes affected by ALS and/or FTD make an impact on axonal structure and function, potentially leading to neuronal cell death (Figure 2). In accordance with this hypothesis, oligodendrocytes derived from ALS patients carrying disease-related mutations in SOD1, TARDBP, C9orf72, or FIG4 phosphoinositide 5-phosphatase induced in vitro neuronal hyperexcitability and subsequent motor neuron cell death (Ferraiuolo et al., 2016). Mice and zebrafish expressing SOD1^G93A specifically in mature oligodendrocytes (oligo-SOD1^G93A mice and zebrafish) showed a reduction in axonal conduction velocity and neuromuscular transmission, as well as progressive axonal degeneration (Kang et al., 2013; Kim et al., 2019). Another mouse model lacking optineurin in mature oligodendrocytes did not exhibit any defect in the number and morphology of spinal cord motor neurons but showed swollen motor axons and muscle denervation, reminiscent of the axonal pathology observed in ALS patients at early disease stages (Ito et al., 2016). Similarly, fast and slow axonal transport was reduced in mice expressing mutant Tau protein specifically in oligodendrocytes, triggering an age-dependent motor deficit that preceded neurodegeneration (Higuchi et al., 2005). Additional studies showed that mice expressing the FTD-linked MAPT mutation P301 exhibited dysmorphic ad-axonal myelin lamellae and impaired conduction of action potentials, which could account for the loss of performance in the object recognition test used to assess learning and memory in these mice (Jackson et al., 2018).

Inwardly rectifying Kir4.1 channels, normally expressed by oligodendrocytes (and astrocytes), are responsible for the clearance of excess accumulation of K⁺ in the extracellular space and contribute to the regulation of neuronal excitability (Schirmer et al., 2018). The expression of Kir4.1 channels was decreased in the spinal cord of SOD1^G93A rats, particularly in regions exhibiting degenerating motor neurons and dysmorphic oligodendrocytes. It was postulated that the reduction of inward currents observed in cultured oligodendrocytes derived from these animals could compromise proper axonal conduction (Peric et al., 2021). The expression of connexins Cx47 and Cx32, implicated in transferring excess extracellular K⁺ between oligodendrocytes and astrocytes, was also reduced in oligodendrocytes in the ventral horns of the spinal cord of SOD1^G93A mice, especially in those containing accumulated mutant SOD1 (Cui et al., 2014), which further reinforces the notion of a defective buffering of K⁺ in the extracellular environment surrounding motor neurons. Altering the functionality of voltage-gated K⁺ channels represents another way of affecting the propagation of axonal action potentials. Oligo-SOD1^G93A zebrafish developed behavioral and learning abnormalities and motor defects in the early symptomatic stage associated with an impaired axonal conduction capacity, and this phenotype was ameliorated by administering the pan voltage-gated K⁺ channel inhibitor 4-aminopyridine (Kim et al., 2019), highlighting the pathological influence of genetically altered oligodendrocytes on global neuronal activity.

Monocarboxylate transporter 1 (MCT1) is the most important monocarboxylate transporter expressed by oligodendrocytes (and astrocytes) that supplies lactate and other metabolites to axons. MCT1 levels were decreased in the CNS of ALS patients and SOD1^G93A mice and zebrafish (Lee et al., 2012; Philips et al., 2013; Ferraiuolo et al., 2016; Kim et al., 2019). Moreover, the expression of SOD1^G93A in human embryonic kidney cells reduced MCT1 content although only at the protein level, indicating the implication of a post-transcriptional mechanism (Philips et al., 2013). Of note, the conditioned medium obtained from cultured oligodendrocytes lacking MCT1 caused motor neuron cell death in vitro, which was partly restored upon lactate supplementation (Ferraiuolo et al., 2016). On the other hand, the removal of mutant SOD1 from the oligodendrocyte lineage in SOD1^G37R mice increased MCT1 content, delayed disease onset and prolonged lifespan (Kang et al., 2013). Collectively, these findings suggest that the down-regulation of MCT1 observed in patients and related animal models can affect neuronal function and should not be exclusively considered as a consequence of the loss of oligodendrocytes during the pathological process.

Other studies, however, failed to show any implication of oligodendroglial MCT1 in affecting neuronal function. In fact, cultured oligodendrocytes derived from ALS patients carrying a Tardbp mutation did not exhibit any deficit in lactate transport (Barton et al., 2021). In addition, the AAV-mediated delivery of MCT1 to mature oligodendrocytes did not provide functional rescue nor survival benefit to SOD1^G93A mice (Eykens et al., 2021). Deleting Mct1 specifically in mouse oligodendrocytes caused a very modest axonal damage not noticed until two years of age (Philips et al., 2021). Finally, an axonopathy similar to that observed in ALS was detected in mice by 8 months of age only after the heterozygous deletion of Mct1 in all cells (Lee et al., 2012). These findings strongly suggest that the role of MCT1 in supplying metabolic support could result from its expression in other cell types, such as astrocytes. Alternatively, the presence of MCT1 in non-myelinating perineuronal oligodendrocytes, which seem to resist to the pathological process, could also play a relevant role in maintaining the metabolic support to neurons (Rohan et al., 2014).

Glutamine synthetase is responsible for the synthesis of glutamine, which is in turn converted into glutamate as part of the glutamate/glutamine cycle that maintains appropriate glutamate concentrations to allow neuronal excitability but, at the same time, impede excitotoxicity. Besides the major contribution of astrocytes, it has been recognized that oligodendrocytes can also participate in the regulation of this cycle. Interestingly, the number of mature oligodendrocytes expressing glutamine synthetase was increased in the ventral spinal cord of SOD1^G93A mice from the pre-symptomatic to end stage, and it was suggested that the resulting accumulation of glutamine could lead to the production of glutamate in excess and subsequent excitotoxicity (Haim et al., 2021).

The histological analysis of post-mortem samples of spinal cord from ALS patients allowed the establishment of four neuropathological stages defined according to the extension of TDP43 inclusions. The regional localization of these inclusions strongly suggested a possible propagation of TDP43 aggregates from gray matter oligodendrocytes to neurons and to white matter oligodendrocytes (Brettschneider et al., 2014; Fatima et al., 2015). Consistent with this notion, the overexpression of TARDBP in cultured oligodendrocytes, when the proteasome was inhibited, led to the formation of cytoplasmic aggregates containing TDP43 that were able to spread into contiguous cells (Ishii et al., 2017). In vivo studies also reported that the unilateral inoculation of homogenates derived from tauopathy patients in the lateral corpus callosum of mice resulted in the pathological aggregation of Tau protein in oligodendrocytes and the spreading of these aggregates from the injection site to the contralateral corpus callosum (Ferrer et al., 2019). In addition, the time course of the chimeric expression in the mouse spinal cord of fluorescent SOD1^G85R showed the transfer of mutant SOD1 between motor neurons as well as between motor neurons and gray matter oligodendrocytes. Since the highest degree of protein transfer occurred when oligodendrocytes deployed their projections toward axons, it was suggested that oligodendrocytes could mediate the propagation of pathogenic proteins between motor neurons (Thomas et al., 2017). Last but not least, the co-culture of naive motor neurons with oligodendrocytes derived from ALS patients triggered the death of motor neurons likely via cell-to-cell contacts or, at least, when the two cell types were in close vicinity (Ferraiuolo et al., 2016). In fact, mature oligodendrocytes are able to release exosomes containing SOD1 that then are internalized by neurons. Under physiological conditions, this mechanism enhances the neuron’s tolerance toward oxidative stress, but it can be postulated that such a mechanism could also account for cell-to-cell propagation of pathological SOD1 in an ALS context (Fröhlich et al., 2014). Taken together, these findings further reinforce the implication of oligodendrocytes in disease propagation.