By Ana Espino | Published on June 19, 2026 | 4 min read
Charcot-Marie-Tooth disease (CMT) is the most common
inherited peripheral neuropathy. It is characterized by progressive damage to
motor and sensory nerves, leading to muscle weakness, sensory impairment, and
walking difficulties. Although more than 130 genes have been identified as
contributors to this disorder, the mechanisms explaining why certain peripheral
neurons are particularly vulnerable remain poorly understood.
In a review published in Cells, researchers propose a
new perspective on CMT associated with mutations in the HSPB1 gene, one
of the known causes of axonal forms of the disease. According to the authors,
the condition does not result solely from a genetic defect but rather from a
complex interaction between genetic predisposition and environmental
stressors. Peripheral neurons, which are exposed throughout life to
significant mechanical, metabolic, and environmental challenges, may be
especially susceptible to this harmful combination.
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Three Mechanisms at the Core of Neuronal Vulnerability
The authors describe three major pathological pathways that
may contribute to the progressive degeneration of peripheral neurons.
The first involves impaired protein quality control.
Under normal conditions, HSPB1 functions as a molecular chaperone, helping to
prevent the accumulation of abnormal proteins during periods of cellular
stress. Mutations in HSPB1 disrupt this protective role, promoting the buildup
of misfolded proteins and impairing the autophagy pathways responsible for
their clearance.
The second mechanism concerns disruption of the neuronal
cytoskeleton. HSPB1 mutations interfere with the stability of microtubules
and neurofilaments, structures that are essential for transporting nutrients,
proteins, and organelles along axons. This disruption progressively compromises
the function of the longest nerve fibers, particularly those supplying the
lower limbs.
Finally, the researchers highlight mitochondrial
dysfunction. Mitochondria, the primary energy producers of neurons, exhibit
abnormalities in transport, dynamics, and quality control. These energy-related
disturbances further increase neuronal vulnerability to physiological stress.
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Toward Intervention Before Symptoms Appear
One of the key messages of this review is that these
cellular abnormalities appear to develop long before the first clinical
symptoms emerge. The authors therefore support the concept of a “prodromal
phase,” during which pathological processes are already active while
patients remain asymptomatic. This period could represent a particularly
valuable therapeutic window for slowing or preventing nerve degeneration.
Several potential therapeutic strategies are discussed,
including the development of compounds capable of restoring autophagy,
correcting abnormal HSPB1 interactions, or using antisense oligonucleotides
targeting mutant forms of the protein. The authors also emphasize the potential
of artificial intelligence to identify early biomarkers and accelerate
the discovery of new treatments.
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A New Way of Understanding the Disease
This review proposes a paradigm shift in the understanding
of certain forms of Charcot-Marie-Tooth disease. Rather than viewing the
genetic mutation as the sole driver of disease progression, the authors suggest
that degeneration results from the gradual inability of neurons to adapt to the
multiple stressors they encounter throughout life.
This perspective opens the door to early neuroprotective
strategies aimed at preserving neuronal homeostasis before irreversible
damage occurs. Such approaches could ultimately transform the management of
inherited peripheral neuropathies by focusing not only on the genetic defect
itself but also on the cellular resilience mechanisms that determine neuronal
survival.
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About the author – Ana Espino
PhD in Immunology, specialized in Virology
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions. 
