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Annals of Clinical Case Reports
Remedy Publications LLC., | http://anncaserep.com/ 2024 | Volume 9 | Article 2666
Astrocytes, SOD1 and Amyotrophic Lateral Sclerosis:
Mechanisms and Implications in Neurodegeneration
Review Article
Published: 28 Aug, 2024
Abstract
As life expectancy increases, brain aging also rises, leading to cognitive and motor function decline.
e accumulation of senescent glial cells during brain aging contributes to chronic inammation
and diseases such as Amyotrophic Lateral Sclerosis (ALS). ese cells, including astrocytes, can
undergo molecular and functional changes, exacerbating inammation and inducing neuronal
toxicity through the secretion of toxic factors, contributing to a pathogenic autotoxic cycle that
drives disease progression. ALS, a severe neurodegenerative disease with reduced life expectancy,
presents symptoms such as muscle atrophy, stiness, and weakness due to motor neuron loss.
ALS can be sporadic or familial, both linked directly or indirectly to Cu/Zn Superoxide Dismutase
(SOD1) enzyme dysfunction. In addition to its role in eliminating superoxide radicals largely
generated by respiration, SOD1 has been described as a possible transcription factor responsible
for activating antioxidant protection mechanisms against oxidative stress. It is also implicated in
signaling that shis respiratory metabolism to aerobic glycolysis (glucose fermentation even in the
presence of oxygen), aecting cellular protection against oxidative stress and longevity. Studies
in animal models and post-mortem analyses of ALS patient tissues have demonstrated specic
alterations in astrocytes, including changes in gene expression and secretion of pro-inammatory
factors. In summary, astrocytes play a complex and signicant role in ALS, directly inuencing
disease progression through inammatory processes, mitochondrial dysfunction, and oxidative
stress. Better understanding of the roles of SOD1 and astrocytes in ALS pathogenesis is crucial for
developing targeted therapeutic strategies aimed at modulating their protective and inammatory
functions.
Keywords: Astrocyte; Superoxide dismutase 1; Amyotrophic Lateral Sclerosis and
neurodegeneration
Queiroz DD and Eleutherio ECA*
Department of Biochemistry, Institute of Chemistry, Federal University of Rio de Janeiro (UFRJ), Brazil
OPEN ACCESS
*Correspondence:
Elis Cristina Araujo Eleutherio,
Department of Biochemistry, Institute
of Chemistry, Federal University of
Rio de Janeiro (UFRJ), Av. Athos da
Silveira Ramos, 149, Rio de Janeiro,
RJ, 21941-909, Brazil, Tel: +55-21-
3938-7735;
Received Date: 24 Jul 2024
Accepted Date: 23 Aug 2024
Published Date: 28 Aug 2024
Citation:
Queiroz DD and Eleutherio ECA.
Astrocytes, SOD1 and Amyotrophic
Lateral Sclerosis: Mechanisms and
Implications in Neurodegeneration. Ann
Clin Case Rep. 2024; 9: 2666.
ISSN: 2474-1655.
Copyright © 2024 Eleutherio ECA. This
is an open access article distributed
under the Creative Commons Attribution
License, which permits unrestricted
use, distribution, and reproduction in
any medium, provided the original work
is properly cited.
Introduction
Aging is an inevitable consequence for all individuals, leading to a decline in cognitive and motor
functions. According to the World Health Organization (WHO), the global population over 60
years old could reach 2 billion by 2050, resulting in a higher incidence of age-related diseases as well
as neurodegenerative diseases such as Parkinson’s, Alzheimer’s, Huntington’s, and Amyotrophic
Lateral Sclerosis (ALS). Although ALS has a low global incidence, it aects approximately 1 to 4 per
100,000 people per year [1] and is recognized as the most severe among neurodegenerative diseases,
with a life expectancy of 2 to 5 years aer disease onset [2]. It is characterized by the progressive loss
of upper and lower Motor Neurons (MNs). is neuronal death leads to progressive weakness and
muscle atrophy, substantially reducing the quality of life for patients, and the majority of patients
die from respiratory failure due to the weakening of respiratory muscles.
Although the majority (~90%) of ALS cases arise sporadically, the remaining proportion suggests
a genetic basis and may provide insights into the pathophysiology, encouraging research into the
genetic causes of this disease. Familial ALS (fALS) accounts for 10% of total cases and is linked to
mutations in more than forty genes. e most common include Superoxide Dismutase 1 (SOD1),
TAR DNA-binding Protein 43 (TDP-43), Fused in Sarcoma (FUS), and C9orf72 [3]. Collectively,
these four genes are responsible for 60% of fALS cases and 11% of sporadic ALS (sALS) cases, with
SOD1 responsible for 12% and 2% of fALS and sALS cases, respectively [4]. However, mutations in
the SOD1 are the second most common genetic cause since the discovery of its association with ALS
over 30 years ago [5]. More than 180 mutations in SOD1 have been described, and these mutations
in the antioxidant enzyme Cu/Zn superoxide dismutase lead to changes in protein folding and
function. An important pathological feature of ALS is the presence of insoluble protein aggregates
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Queiroz DD, et al., Annals of Clinical Case Reports - Medicine
Remedy Publications LLC., | http://anncaserep.com/ 2024 | Volume 9 | Article 2666
of misfolded proteins that tend to accumulate in motor neurons and
associated glial cells [6].
SOD1 and ALS
SOD1 encodes a ubiquitously expressed cytosolic enzyme
with a molecular mass of 32 kDa, consisting of two subunits, each
composed of 153 amino acids, one copper ion (Cu2+), and one zinc
ion (Zn2+) per active site. Its normal cellular function is to detoxify
superoxide produced in the mitochondrial intermembrane space,
cytosol, and peroxisomes, converting it into oxygen and hydrogen
peroxide, thereby serving as an important cellular antioxidant
defense mechanism. Although this is its primary function, recent
studies have shown that SOD1 has other functions that diverge from
this original role, including the activation of protective and repair
gene transcription following exposure to oxidative stress and the
modulation of glucose sensing pathways to regulate metabolic type,
whether fermentative or respiratory [7].
All these functions performed by SOD1 are crucial for the proper
functioning of neurons. Neurons are highly susceptible to oxidative
stress and therefore depend on the ecient performance of the
antioxidant system, in which SOD1 acts as a catalyst and inducer
of the antioxidant response. On the other hand, neurons rely on
lactate produced by astrocytes to generate ATP, conserving glucose
for NADPH production for their antioxidant protection. SOD1 has
also been described as a regulator of aerobic glycolysis. However,
mutations such as hSOD1A4V have been shown to inadequately
regulate PDH activity through phosphorylation, impairing aerobic
glycolysis a process crucial in astrocytes and vital for neuronal health
[8]. erefore, non-functional or misfolded SOD1 poses signicant
harm to neurons [7]. In some cases of ALS, altered SOD1 protein
accumulates within associated neuronal and non-neuronal cells,
believed by researchers to cause neuronal damage leading to their
death. It is important to note that normal SOD1 protein, present in
sALS, can also generate protein aggregates, suggesting this is a central
issue in ALS. Recently, it has been shown that various forms of SOD1
proteopathy are a common feature in all forms of ALS (sporadic and
familial, whether or not linked to SOD1 mutations) [9]. Most of these
alterations are specic to regions of neurodegeneration, emphasizing
the importance of SOD1 proteopathy as a target for developing new
therapies against ALS. Rodent models expressing missense mutations
in SOD1 develop abnormal cytoplasmic protein aggregates and motor
neuron degeneration, identical to human SOD1-ALS pathology, while
SOD1 knockout mice fail to develop aggregates and NM loss [10].
is has also been observed with TDP-43 inclusions in neural and
glial cells inducing degenerative motor neuron death in ALS through
the pathogenic eect of TDP-43 protein resulting from the formation
of toxic aggregates, rather than loss of function. It is known that TDP-
43 inclusions are found in 95% of motor neurons and glia in ALS
patients, and aggregation occurs due to phosphorylation controlled
by the phosphatase Calcineurin (Cn) [11]. Previous in vivo and in
vitro studies have shown that SOD1 interacts with Cn increasing its
activity, consequently hyperphosphorylating TDP-43 [12]. Jeon and
collaborators demonstrated that the expression and redistribution
of TDP-43 protein in neurons and glial cells of SOD1G93A mice
lead to cellular damage and death, indicating that SOD1 mutations
alter modications as well as phosphorylation in TDP-43, thereby
supporting the hypothesis of an interaction between mutant SOD1
and TDP-43 in ALS pathogenesis [13]. However, further studies are
needed to clarify the mechanism of TDP-43 modication induced by
SOD1 mutation.
Pathogenic Mechanisms in ALS
Although many pathophysiological mechanisms have been
proposed, such as excitotoxicity, oxidative stress, mitochondrial
dysfunction, protein aggregation, and neuroinammation, it is
increasingly evident that ALS is not a disease purely related to motor
neurons; both astrocytes and SOD1 mutations play crucial roles in
these processes. e central nervous system (CNS), traditionally
divided into the brain, spinal cord, and retina, is composed of
neuronal and glial cells. Glia consists of astrocytes, microglia, and
oligodendrocytes in the central nervous system, and satellite glial cells
and Schwann cells in the peripheral nervous system. However, glial
cells also play a role in neuroinammatory mechanisms and neuronal
death throughout the progression of the disease [14-16].
Role of Astrocytes in ALS
ALS is a complex and multifactorial disease, indicating that
the crosstalk among dierent cell types contributes to triggering
neurodegeneration rather than a single cell type. Astrocytes are
the largest population of non-neuronal cells in the CNS and
perform a wide range of functions in a healthy brain. Astrocytes
express receptors, transporters, and neurotransmitters, in addition
to releasing neurotrophic factors, inammatory mediators, and
cytokines. erefore, astrocytes are crucial for providing structural,
metabolic, and trophic support to neurons [17].
In response to a wide variety of stimulus and the context in
which they nd themselves, as well as during neurodegeneration,
astrocytes can signicantly alter their gene expression, morphology,
and function in a process known as "reactivity," which can present
neurotoxic, pro-inammatory (A1) or neuroprotective, anti-
inammatory (A2) phenotypes [18-20]. Reactive astrogliosis is
driven by inammatory signals, loss of neuronal contact, and
disease-associated proteinopathy [19,21]. For example, during aging,
reactive A1 astrocytes exhibit altered morphologies and produce pro-
inammatory cytokines, leading to neuroinammation, a process
that plays a signicant role in the CNS and associated pathological
conditions [22]. In degenerative disorders, such changes disrupt
brain homeostasis, causing astrocytes to acquire toxic gain-of-
function or loss of essential metabolic functions that exacerbate
neurodegenerative processes [23]. In astrocytes-ALS, evidence of
both neuroprotective and neurotoxic eects has been reported [24].
It is well known that astrocyte dysfunction and neuroinammation
have been shown to accompany and likely even drive the loss of
motor neurons in ALS. However, the role of reactive astrocytes in the
progression of ALS involves several mechanisms that can result in the
loss of physiological and homeostatic functions or the acquisition of
a neurotoxic and aberrant phenotype [6,25]. For example, reactive
astrocytes in ALS show increased immunoreactivity for GFAP
and the calcium-binding protein S100β, expressing inammatory
agents such as cyclooxygenase-2, inducible nitric oxide synthase
(iNOS), NOS and reactive oxygen species (ROS). Furthermore, C3,
a recognized marker of A1 astrocytes, has been identied in post-
mortem tissue from the cortex and spinal cord of ALS patients, both
in cases of fALS and sALS [19,26]. However, the mechanisms that
lead to astrocytic failure and hyperactivation remain unclear. us,
identifying specic mechanisms and mediators of astrocytic toxicity
may provide important insights into the pathways of motor neuron
degeneration in ALS.
As observed, this spontaneous neurodegenerative phenotype has
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Remedy Publications LLC., | http://anncaserep.com/ 2024 | Volume 9 | Article 2666
been reported in results widely described in the literature, as well as
the toxic eect on motor neurons (MNs). e presence of specic
soluble factors from mutated astrocytes is sucient to induce damage
and loss of MNs, as observed when they were cultured in the presence
of primary astrocytes expressing SOD1G93A or when exposed to
astrocyte-conditioned medium (ACM) [27-30], as well as in ALS
patients [31].
More evidence indicates that astrocytes in ALS exhibit
dysfunctional mechanisms and actively induce toxicity in MNs.
Among these mechanisms, selective impairment of glial glutamate
transport, leading to the accumulation of excitotoxic levels of
extracellular glutamate, is one of the earliest hypotheses proposed to
explain MN death in ALS. Astrocytes maintain homeostatic levels of
extra-synaptic glutamate within the synaptic cle to regulate synaptic
transmission, primarily through specic glutamate transporters
such as GLAST and GLT-1 [32]. e GLT-1 transporter is found
exclusively in astroglia, both in the brain and spinal cord, and is
responsible for the uptake of nearly 90% of glutamate. If glutamate
is not removed, activation of glutamate receptors leads to sustained
elevation of intracellular calcium levels in neurons, initiating a
cascade of events that culminate in cell death. Astrocytes expressing
mutant hSOD1 have shown impaired glutamate clearance, suggesting
a pathological feature of the disease [33-35]. erefore, signicant
changes in astrocyte biology accompany MN degeneration in ALS
models, further supporting the idea that astrocytes play an active role
in toxicity mediated by mutant hSOD1.
Finally, the ability of astrocytes to produce and provide energy
metabolites and antioxidants is essential for normal neuronal
metabolic function [36-38]. Neuronal activity is a process with high
energy demands, and through the lactate shuttle from astrocytes to
neurons, lactate derived from astrocytes supports the energy needs of
neurons. Additionally, glutathione metabolism in astrocytes enhances
neuronal antioxidant defenses and protects neurons from increased
oxidative stress resulting from neurotransmission and metabolic
activity [38]. Dysregulation of this astrocyte-neuron coupling, crucial
for normal brain function, likely contributes to neuronal death during
neurodegeneration.
Taken together, these studies suggest a scenario of disrupted
cell-cell communication with NM being the primary target of the
toxicity of the mutant hSOD1, and glial cells modulating the rate of
degeneration. By carrying the hSOD1 mutation, nearby glial cells
damage motor neurons, as well as other important partner cells, which
likely adopt aberrant responses and accelerate disease progression.
Together, these observations suggest that NM degeneration mediated
by astrocytes is an important phenomenon in ALS, but we believe
that further studies are necessary to better understand the role of
astrocytes in this disease.
Intersection between Astrocytes, SOD1, and
Neurodegeneration
e intersection between astrocytes, SOD1, and
neurodegeneration in ALS reveals a pathogenic cycle where the
dysfunction/gain of function of astrocytes and SOD1 enhances
neuronal toxicity, perpetuating neurodegeneration. As mentioned,
in neurodegenerative diseases such as ALS, astrocytes change their
morphology and function and then become reactive in response to
various stimulus.
As previously reported, the rst gene identied related to ALS
was SOD1, which led to the proposal of several relevant mechanisms
in the pathogenesis of the disease. Although the cause is still unclear,
we know that mechanisms such as excitotoxicity, oxidative stress,
endoplasmic reticulum (RE) stress, mitochondrial dysfunction,
disruption of axonal transport, prion-like propagation, and non-cell
autonomous toxicity from glia are associated with SOD1 proteopathy.
Post-mortem isolated astrocytes from ALS or fALS patients have been
considered toxic to healthy motor neurons in culture, but this toxicity
is alleviated by reducing SOD1 expression in astrocytes [39,40].
Reactive astrocytes induce neurolaments and SOD1 aggregation,
disrupting autophagy via TGF-β1 action, leading to motor neuron
degeneration [41]. SOD1G93A astrocytes are larger than those from
normal tissue, with more hypertrophied processes and express typical
markers of astrogliosis, including GFAP [34,42]. Additionally, the
expression of Connexin 43 (Cx43), an important astrocytic connexin
that drives crucial homeostatic functions in the CNS, is elevated in
SOD1G93A astrocytes. During the pre-symptomatic stages of ALS,
Cx43 expression in astrocytes is slightly elevated above physiological
levels, and this elevation becomes more signicant as the disease
progresses [43]. erefore, signicant changes in astrocyte biology
accompany the degeneration of motor neurons in ALS models,
reinforcing the idea that astrocytes play an active role in toxicity
mediated by mutant hSOD1.
It is clear that many studies have implicated astrocytes in the
pathogenesis of ALS. Recently, changes in the expression of genes
associated with extracellular matrix dynamics, endoplasmic reticulum
stress responses, and the immune system were reported in a meta-
analysis of studies involving human iPSC-derived astrocytes with
SOD1 mutations and astrocytes from mice expressing the SOD1G93A
mutation [44]. Another recent study, published by Shen and
collaborators assessed the function of Dierentially Expressed Genes
(DEGs) in non-neuronal cells from the primary motor cortex of ALS
patients. e results showed that the functions of the DEGs in non-
neuronal cells were primarily related to energy metabolism, especially
oxidative phosphorylation, and protein synthesis. Additionally,
SOD1 was positively regulated in glial cells, conrming that it could
be a potential biomarker [45]. Abnormal oxidative phosphorylation
is associated with the development of ALS. Analysis of transcriptomic
datasets from humans and mice obtained from the GEO database
revealed that oxidative phosphorylation was dysregulated in data
from ALS patients and in models of mice transgenic for SOD1 [46].
Furthermore, it was observed that the genes involved in oxidative
phosphorylation encoded by nuclear DNA showed heterogeneous
expression, mostly decreased in the spinal cord tissue of ALS patients
[47].
Glial cells are considered one of the largest producers of ROS and
reactive nitrogen species (RNS) under pathological conditions in the
CNS, including motor neuron diseases [48]. An increase in cellular
respiration contributes to elevated ROS levels in astrocytes, activating
an inammatory response that results in non-cell autonomous
degeneration of motor neurons. We know that the regulation of
the redox balance between astrocytes and neurons is determined
by the equilibrium between GSSG/GSH, NAD/NADH, and NADP/
NADPH, which directly aects the balance of metabolites such as
lactate and pyruvate, and β-hydroxybutyrate and acetoacetate, whose
interconversion depends on these ratios. Studies have shown that
GSH levels are lower in the motor cortex of ALS patients compared
to healthy volunteers [49]. In hSOD1G93A and hSOD1WT mice, it
has been demonstrated that GSH depletion promotes neurological
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Remedy Publications LLC., | http://anncaserep.com/ 2024 | Volume 9 | Article 2666
decits, mitochondrial pathology, and motor neuron degeneration
[50,51]. In ALS, signicant eorts have provided deep insights into
the dysregulated secretome of astrocytes. Recently, an analysis of
the proteome and metabolite secretome of astrocytes expressing
hSOD1G93A showed alterations in GSH metabolism and signaling
that were negatively regulated, while proteolytic processes were
positively regulated [52]. In summary, astrocytes express and release
antioxidants as part of their function in regulating redox balance by
removing ROS to prevent oxidative damage to neurons [53].
Finally, we know that misfolded proteins are transmitted
between cells in neurodegenerative diseases, particularly with SOD1
in ALS. Several studies have described "prion-like" characteristics of
misfolded SOD1, including its ability to transfer between cells, causing
the misfolding of wild-type SOD1 within those cells. Astrocyte-
neuron communication can also be modulated by the secretion of
extracellular vesicles (EVs), such as microvesicles and exosomes.
Misfolded SOD1, whether wild-type or associated with mutations, is
secreted via EVs in NSC-34 and HEK cells [54]. EVs containing SOD1
aggregates have also been found in the plasma of fALS patients [55],
as well as in the brains and spinal cords of SOD1G93A mice, where
they were eciently transferred to spinal neurons, inducing selective
motor neuron death [56,57], further reinforcing their involvement
in the pathogenesis of the disease. As observed, alterations in the
production and composition of exosomes in astrocytes have been
previously reported in ALS [58]. Recently, a study demonstrated that
exosomes derived from SOD1G93A astrocytes are sucient to reduce
the survival of MN as well as the length and branching of neurites
[59]. However, the transmission of toxic aggregates via EVs is still
not well understood.
Taken together, all these data demonstrate that the dysfunction of
the astrocytic secretome in ALS impairs many key functions of motor
neurons involving autophagy, growth, and neurite length, resulting
in accelerated protein aggregation, excitotoxicity, cellular stress and
degeneration [60].
Concluding Remarks
Based on the factors leading to the gain of function/dysfunction
of SOD1, the role of astrocytes in neurodegeneration, and their
correlation in the pathogenesis of ALS, this review aims to understand
the altered molecular pathways that may underlie the dysfunctions of
astrocytes in ALS and the altered astrocyte-motor neuron crosstalk
in the pathology. Collectively, astrocytes play a signicant role in
the pathology of ALS in humans and in mouse models, aecting
various cell types, particularly MNs, whose survival is severely
compromised by astrocytic inuence. erefore, there is growing
evidence that both astrocytes and SOD1 are important contributors
to neurodegeneration. Understanding the processes occurring in the
damaged central nervous system is crucial for developing therapies
that may improve the prognosis and quality of life for patients aected
by this devastating neurodegenerative disease.
Funding
is work was supported by grants from FAPERJ (CNE
201.174/2022), CAPES-DAAD (PROBRAL 88881.371325/2019-01)
and CNPq Universal (401780/2023-6).
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