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Biochemical dissection of STAT3
signaling in amyotrophic lateral
sclerosis
Savina Apolloni , Nadia D’Ambrosi
2025, 20 (11):
3229-3230.
doi: 10.4103/NRR.NRR-D-24-00862
Amyotrophic lateral sclerosis (ALS) is a progressive
neurodegenerative disease characterized by the
loss of upper and lower motor neurons, clinically
marked by muscle atrophy and weakness.
Although the clinical course is highly variable,
the average time from the onset of symptoms
to the need for respiratory support or death
is 3–5 years. ALS is the most prevalent motor
neuron disease in adults, occurring at a rate of
2 per 100,000 individuals and affecting 5.4 per
100,000 individuals overall. At present, there is no
established effective treatment for ALS; riluzole (an
antagonist of glutamate neurotransmission) and
edaravone (a superoxide scavenger) are the only
drugs approved for use in the treatment of ALS,
and both produce only slight beneficial effects
in a limited population of ALS patients. Tofersen,
a recently US Food and Drug Administrationapproved
antisense oligonucleotide, is only
for patients carrying SOD1 mutation (Mead et
al., 2023). Despite ALS has a significant genetic
component with high heritability, many gene
variants responsible for or contributing to the
disease remain unidentified. The involvement of
numerous cellular processes in ALS progression
complicates the identification of causative factors.
The complexity of the disease and the extensive
genetic and phenotypic diversity among patients
hinder the translation of findings from animal
models to successful human clinical trials. 5%–10%
of ALS cases are classified as familial ALS based
on family history. The genes most associated
with familial ALS include C9ORF72, TARDBP, FUS,
and SOD1. Recent genetic studies have identified
various mutations in sporadic ALS cases, suggesting
potential genetic contributors to the disease. These
risk genes implicate pathways such as apoptosis
due to mitochondrial dysfunction, autophagy with
disrupted protein homeostasis, inflammation (both
peripheral and central), impaired intracellular
trafficking, and excitotoxicity. These dysfunctional
pathways affect multiple cell types, including
upper (corticospinal) and lower (spinal) motor
neurons, associated glial and Schwann cells,
skeletal muscle fibers and their progenitors, and
immune/inflammatory cells. Among the genes
most specifically associated with ALS and muscle
atrophy retrieved by BenevolentAI Knowledge
Graph, of particular interest is signal transducer
and activator of transcription-3 (STAT3), which is
among the five genes contributing to common
ALS disease mechanisms such as autophagy,
apoptosis, cytokine signaling and the FOXO
signaling pathway, underscoring the central role
of STAT3 signaling in the disease. Furthermore,
beyond inflammation, autophagy, apoptosis,
and the FOXO pathways, Janus kinase (JAK)/STAT
signaling is heavily implicated in the distinctive
pathophysiology of ALS. This includes aspects
such as TAR DNA-binding protein 43 (TDP-43)
protein aggregation, mitochondrial dysfunction,
skeletal muscle denervation, and excitotoxicity.
These disease processes are widely recognized as
major contributors to ALS pathology, particularly
mitochondrial dysfunction leading to ATP deficits
and protein aggregation, with TDP-43 aggregates
present in 95% of patients, along with muscle
denervation and atrophy culminating in fatality.
The revelation that all these pathways involve JAK/
STAT signaling implies that targeting this pathway
could hold therapeutic promise (Richardson et al.,
2023).
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