Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting the motor nerves. At present, there is no effective therapy for this devastating disease and only one Food and Drug Administration (FDA)-approved drug, riluzole, is known to moderately extend survival. In the last decade, the field of ALS has made a remarkable leap forward in understanding some of the genetic causes of this disease and the role that different cell types play in the degenerative mechanism affecting motor neurons. In particular, astrocytes have been implicated in disease progression, and multiple studies suggest that these cells are valuable therapeutic targets. Recent technological advancements have provided new tools to generate astrocytes from ALS patients either from post-mortem biopsies or from skin fibroblasts through genetic reprogramming. The advent of induced pluripotent stem cell (iPSC) technology and the newly developed induced neural progenitor cells (iNPCs) have created unprecedented exciting opportunities to unravel the mechanisms involved in neurodegeneration and initiate high-throughput drug screenings.

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by death of upper and lower motor neurons, which results in muscle wasting and death from respiratory failure typically within 2–5 years of diagnosis.

ALS is a multifactorial disease [1] where different cell types, i.e. astrocytes, neurons, microglia and oligodendrocytes, contribute to the pathological mechanism [2,3]. For a long time, ALS was thought to be a pure motor neuron disease; however, thorough pathological investigations and recent findings linking mutations in transactive response DNA-binding protein (TARDBP) gene to familial (fALS) and sporadic (sALS) cases of ALS have relocated this disease within a spectrum of neurological disorders, ranging from pure motor neuron disease to frontotemporal dementia [4,5].

Since 1993, when the first mutation in the Cu/Zn superoxide dismutase 1 (SOD1) enzyme was linked to familial forms of ALS [6], researchers have tried to unravel the mechanisms underlying this disease by interrogating in vivo and in vitro models overexpressing mutant human SOD1 (mSOD1). Although these models have highly contributed to understanding the pathogenic mechanisms involved in motor neuron degeneration, they account only for less than 2% of all cases. Hence the ALS field is still lacking effective therapies and a deep understanding of the aetiology of the sporadic disease.

For 15 years, the SOD1 models were the only available, until, in 2008, mutations in TARDBP were found to be responsible for familial and sporadic forms of ALS [7,8]. This led to the discovery that mutations in a second RNA/DNA-binding protein, called fused in sarcoma (FUS) or translocated in liposarcoma (TLS), were also cause of the disease [9,10]. More recently, the field of ALS has seen a breakthrough with the association of GGGGCC hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) with 35–40% of fALS cases and 5–7% of sALS cases [1113].

Although the clinical features of ALS are determined by the progressive and inexorable degeneration of motor neurons, in the last decade it has become clear that non-neuronal cells are not only affected by the pathogenic mechanisms occurring in ALS, but also play a crucial role in motor-neuron death. These developments led to the concept that motor-neuron death in ALS is a non-cell-autonomous process.

Experiments using chimaeric mice highlighted the role that different cell types play in determining onset or progression of disease. Transgenic mice expressing the Cre/Lox recombination system to exclude mSOD1 from motor neurons or non-neuronal cells showed that silencing of the transgene in motor neurons can delay disease onset [14], whereas removal from microglia [14] or astrocytes [15] can only slow down disease progression. Hence the onset of the disease and its subsequent progression and propagation probably represent two separate phases of disease, characterized by different mechanisms, and thus providing distinct possibilities for therapeutic intervention.

From 2007 to the present, in vitro technologies to model neurological disorders have also undergone an impressive development. With the discovery that adult human fibroblasts could be reprogrammed to induced pluripotent stem cells (iPSCs) with the use of selected transcription factors [16], the field of ALS saw the opportunity to finally model not only fALS, but also especially sALS in vitro [17]. As a further development of this technique, several protocols have been developed to produce neural progenitor cells (NPCs) [18] or mature cells of neural lineage from mouse and human fibroblasts [1921] without going through the iPSC stage. Moreover, in 2011, NPCs were isolated from post-mortem spinal cord samples of ALS patients, and were successfully cultured and differentiated into motor neurons, astrocytes and oligodendrocytes in vitro [22].

Taken together, the latest genetic discoveries, along with the recent technological developments, have tremendously expanded the horizon of ALS research.

Astrocytes in ALS: gain of toxic function or loss of function?

Several in vitro experiments have demonstrated that primary astrocytes isolated from rodents expressing mSOD1 have toxic effects on cultured primary motor neurons and both embryonic mouse and human stem-cell-derived motor neurons [23,24]. However, no information was available on the properties of human astrocytes from ALS samples untill 2011.

The isolation of NPC from post-mortem spinal cord biopsies from sALS and fALS patients and their subsequent differentiation into astrocytes demonstrated for the first time that human ALS astrocytes are also toxic to motor neurons in vitro [22]. A more recent study confirmed these findings using primary astrocytes also isolated from post-mortem spinal cord biopsies from sALS cases [25].

Although these methodologies provided the possibility to model all forms of ALS in vitro, without inducing major epigenetic alterations, the availability of post-mortem samples suitable for NPC isolation is very limited.

The development of new technologies has also allowed the production of astrocytes from patient fibroblasts through genetic reprogramming [26]. iPSCs have provided a new tool to investigate the non-cell-autonomous component of this disease in a larger variety of genetic subgroups.

One study conducted in astrocytes derived from iPSCs from patients carrying mutations in TARDBP displayed increased levels of protein, subcellular mislocalization and decreased cell survival, thus suggesting that mutant transactive response DNA-binding protein 43 kDa (TDP-43) expression is responsible for astrocyte pathology. Strikingly, nevertheless, these astrocytes were not toxic to wild-type iPSC-derived motor neurons [27].

In agreement with these results, Haidet-Phillips et al. [29] utilized astrocytes isolated from a mouse model expressing mutant TDP-43 under the prion promoter [28] to support lack of non-cell-autonomous toxicity in TDP-43-related ALS cases in vitro. In co-culture, in fact, both astrocytes carrying mutant TDP-43(A315T) and astrocytes lacking TDP-43 did not cause wild-type motor neuron death. Moreover, injection of glial precursors from TDP-43 transgenic mice into the spinal cord of wild-type rats did not result in signs of degeneration or inflammation. Opposite results were obtained when transplanting mSOD1 astrocytes into wild-type rats [30].

In contrast with these findings, a third report using transgenic rats expressing mutant TDP-43 under the glial fibrillary acidic protein (GFAP) promoter showed that restricted expression of mutant TDP-43 is sufficient to induce motor-neuron degeneration in vivo [31]. Several experimental differences might account for these discordant results; however, further studies are needed to better understand the properties of astrocytes from patients carrying mutations in TARDBP, in view of therapeutic approaches.

To overcome some of the limitations of using iPSCs, i.e. lengthy process, Meyer et al. [18] developed a new methodology to reprogramme human fibroblasts. Using the same reprogramming factors employed in iPSC technology, this new method allows the production of induced neuronal progenitor cells (iNPCs) within 3–4 weeks of fibroblast infection. iNPCs can then be differentiated into astrocytes in 1 week and used for experimental assays. With this approach, astrocytes were derived from iNPCs of ALS patients carrying C9orf72 repeat expansion or mutations in SOD1, as well as sporadic patients [18]. This study revealed that astrocytes carrying C9orf72 repeat expansion display a similar toxicity to that of the astrocytes derived from other genetic subtypes of ALS. Therefore the evidence collected from human samples, although preliminary and to be cautiously interpreted, suggests that astrocytes are a common player in the pathogenic mechanisms occurring in most ALS cases.

Moreover, a recent study carried out in parallel in two laboratories, utilizing different mSOD1 mouse models, demonstrated that knocking down mSOD1 in astrocytes, either at early stages or even at symptom onset, is effective in slowing down disease progression and leads to an overall increase in survival rate [32]. Hence astrocytes seem to be a valuable target for ALS therapy.

In the last decade, several mechanisms have been identified in the mSOD1 mouse model of ALS as potential factors of astrocyte toxicity [1]. The finding that conditioned medium from ALS astrocytes also induces motor-neuron death has led to the hypothesis that the toxic factor(s) is secreted [23]. Although several studies focused on identifying the molecules involved in this toxicity [23,3335], other evidence was found, indicating that astrocytes might be contributing to motor-neuron death through a lack of support [36].

Although, at present, the identity of the toxic factor(s) secreted by ALS astrocytes is still unknown, Bax activation has been implicated in the death programme activated by motor neurons growing on ALS astrocytes [23,25]. Other studies focus on the inflammatory characteristics of ALS astrocytes [22] and their uncontrolled release of reactive oxygen species [33,34]. More recently, ion homoeostasis has been implicated as a potential mechanism inducing hyper-excitability in motor neurons and, consequently, death [35].

In contrast, the hypothesis that ALS astrocytes might induce motor-neuron death due to a lack of support is reinforced by their failure in providing metabolic substrates, i.e. lactate [37], and protection from insults, i.e. synaptic glutamate, due to a decrease in the expression of glutamate transporters [38,39]. Both of these mechanisms would not require cell-to-cell contact to induce motor-neuron death. Interestingly, recent reports have highlighted that astrocytes from ALS samples are characterized by aberrant behaviour in multiple pathways that affect their cross-talk with motor neurons [37,40], as well as their physiological characteristics [25,36]. This supports the hypothesis that astrocyte toxicity in ALS is related to both a loss of physiological function and a gain of toxic function that affect this cell type under several different aspects (Figure 1). In this scenario, future therapies will require a multi-target approach in order to both silence the expression of toxic factors and support or reinstate physiological astrocyte function.

Schematic representation of the pathways that have been implicated in ALS astrocyte toxicity against motor neurons

Figure 1
Schematic representation of the pathways that have been implicated in ALS astrocyte toxicity against motor neurons

In red are the mechanisms suggesting that a gain of toxic function might be responsible for astrocyte toxicity with subsequent activation of Bax-dependent cell death. In blue are the mechanisms suggesting that astrocyte toxicity might be due to a loss of function, leading to lack of support or accumulation of toxic factors, thus causing excitotoxicity, cell starvation and hyperexcitability.

Figure 1
Schematic representation of the pathways that have been implicated in ALS astrocyte toxicity against motor neurons

In red are the mechanisms suggesting that a gain of toxic function might be responsible for astrocyte toxicity with subsequent activation of Bax-dependent cell death. In blue are the mechanisms suggesting that astrocyte toxicity might be due to a loss of function, leading to lack of support or accumulation of toxic factors, thus causing excitotoxicity, cell starvation and hyperexcitability.

The role of inflammation and myelination in ALS

Oligodendrocytes and microglia have also been involved in the degenerative process, affecting motor neurons in ALS.

Recent studies have highlighted the importance of oligodendrocytes in providing metabolic support to motor neurons through provision of substrates such as lactate [3]. This pathway was found to be impaired in mSOD1 mice concomitant with oligodendrocyte degeneration and myelination loss [41]. Interestingly, mSOD1 mice do not seem to show myelination defects at birth or during postnatal development; however, the spinal cord shows vast NG2+ cell proliferation in the ventral horn region, even before symptom onset [41]. However, the proliferating NG2+ cells seem to fail to accomplish full maturation, thus leaving large areas demyelinated [41].

Extensive astrocyte and microglial activation and infiltration of peripheral immune cells at sites of motor-neuron degeneration are one of the most-striking hallmarks of ALS shared by familial and sporadic patients, as well as rodent models [42]. Different approaches have been attempted to dampen inflammation in ALS; unfortunately only very mild results, if any, have been obtained, highlighting the complexity of this response [43]. Interestingly, nuclear factor-κB (NF-κB), a master transcriptional regulator of inflammation, is activated in glia in fALS and sALS [44]. Very recently, a genetic approach to silence NF-κB activation in the myeloid lineage of a mSOD1 mouse model of ALS resulted in an outstanding increase in survival [45]. More interestingly, constitutive activation of NF-κB in the myeloid lineage of mice, not carrying any ALS-linked mutation, recapitulated some of the pathological aspects of ALS, including gliosis and motor-function impairment, following motor-neuron death [45]. Although these mice do not follow the same aggressive fatal paralysis as mSOD1 mice, this study shows that chronic inflammation can lead to motor-neuron death even in the absence of ALS-associated mutations, thus proposing a potential causal mechanism for sporadic cases.

In conclusion, a better understanding of the cross-talk between glia and motor neurons should inform therapeutic efforts to slow down or even halt motor-neuron degeneration in ALS.

Modelling ALS and seeking new therapies

The recent remarkable advancement in the cell biology field that adult fibroblasts can be reprogrammed to virtually originate all cell types has created a unique opportunity to model neurological disorders in vitro. iPSC technology has already been applied to several neurodegenerative conditions, from Alzheimer's disease [46] to Down's syndrome [47], as well as schizophrenia [48], Rett syndrome [49] and ALS [17].

Although a large number of iPSC lines from patients affected by various diseases have been made commercially available (http://www.coriell.org/research-services/stem-cells/overview), it is still not clear how robustly these recapitulate the characteristics specific of each disease. Although the promises of iPSC technology are to lead to high-throughput screenings to find new efficacious therapeutic targets, they are subject to some main limitations, i.e. a lengthy process, variability and epigenetic modifications during reprogramming.

However, promising results have been obtained from recent studies suggesting that iPSC-derived motor neurons and astrocytes originated from patients carrying TDP-43 mutations display abnormalities typical of TDP-43 proteinopathy. Motor neurons display elevated levels of soluble and detergent-resistant TDP-43, decreased survival and increased vulnerability to inhibition of the phosphoinositide 3-kinase (PI3K) pathway [50], as well as shorter neurites and TDP-43 cytoplasmic aggregates [51]. These parameters can be used as readout for high-throughput drug screenings, as well as shRNA library screenings. Indeed, Egawa et al. [51] managed to identify drugs that had protective effects against motor-neuron death and TDP-43 cytoplasmic aggregates, and which led to an increase in neurite length.

In contrast, the astrocytes generated by Meyer et al. [18] from iNPCs with a fast conversion method recapitulate the toxic properties displayed by post-mortem astrocytes isolated from ALS patients [22], thus setting the premises for drug and shRNA screening to target pathways and single genes involved in astrocyte toxicity.

This approach could unveil the existence of underlying pathways common to different genetic forms of ALS or, adversely, lead to subgrouping patients according to their responsiveness to different drugs.

In conclusion, it is clear that in the last 5 years, the ALS field has seen a major change of scenario, where more tools are available to study multiple forms of fALS, as well as the striking majority of sALS. Recent genetic discoveries have highlighted the importance of previously unexplored pathways, i.e. RNA metabolism, and common targets linking sALS and fALS have been identified, i.e. TDP-43 and SOD-1. Moreover, the advances in high-throughput screening technology, with the advent of new gene-profiling techniques, i.e. deep-sequencing and high content imaging systems are bound to determine the beginning of a new era for ALS research.

Astrocytes in Health and Neurodegenerative Disease: A joint Biochemical Society/British Neuroscience Association Focused Meeting held at Institute of Child Health, University College London, London, U.K., 28–29 April 2014. Organized and Edited by Jon Cooper (Institute of Psychiatry, King's College London, U.K.), Diane Hanger (King's College London, U.K.), Wendy Noble (King's College London, U.K.), Michael Sofroniew (University of California Los Angeles, U.S.A.), Alexei Verkhratsky (University of Manchester, U.K.) and Brenda Williams (Institute of Psychiatry, King's College London, U.K.).

Abbreviations

     
  • ALS

    amyotrophic lateral sclerosis

  •  
  • C9orf72

    chromosome 9 open reading frame 72

  •  
  • fALs

    familial ALS

  •  
  • iNPC

    induced neural progenitor cell

  •  
  • iPSC

    induced pluripotent stem cell

  •  
  • mSOD1

    mutant human SOD1

  •  
  • NF-κB

    nuclear factor-κB

  •  
  • NPC

    neural progenitor cell

  •  
  • sALS

    sporadic ALS

  •  
  • SOD1

    Cu/Zn superoxide dismutase 1

  •  
  • TARDBP

    transactive response DNA-binding protein

  •  
  • TDP-43

    transactive response DNA-binding protein 43 kDa

Funding

This work was funded by the International Outgoing Marie Curie Fellowship.

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