# Stress-Driven Selective Neuronal Vulnerability in Charcot–Marie–Tooth Disease: From Prodromal Pathology to Therapeutic Implications

## TL;DR

This paper explains how a genetic mutation in HSPB1 leads to Charcot–Marie–Tooth disease by making nerve cells vulnerable to stress, and suggests early treatment could prevent nerve damage.

## Contribution

The paper reframes HSPB1-related CMT as a gene–environment interaction disorder and proposes early therapeutic intervention to prevent neurodegeneration.

## Key findings

- HSPB1-related CMT is caused by the convergence of proteostatic, cytoskeletal, and mitochondrial dysfunction.
- Peripheral neurons are selectively vulnerable due to anatomical and metabolic constraints interacting with HSPB1 mutations.
- Early, pre-symptomatic intervention targeting the HSPB1 interactome could prevent neurodegeneration.

## Abstract

What are the main findings?
HSPB1-related Charcot–Marie–Tooth (CMT) disease is reframed as a gene–environment interaction disorder, where the unique anatomical and metabolic constraints of the peripheral nervous system predispose it to homeostatic failure.Selective neuronal vulnerability arises from the convergence of three interconnected pathological axes (proteostatic disturbance, cytoskeletal dysregulation, and mitochondrial dysfunction), which collectively impair stress adaptability.

HSPB1-related Charcot–Marie–Tooth (CMT) disease is reframed as a gene–environment interaction disorder, where the unique anatomical and metabolic constraints of the peripheral nervous system predispose it to homeostatic failure.

Selective neuronal vulnerability arises from the convergence of three interconnected pathological axes (proteostatic disturbance, cytoskeletal dysregulation, and mitochondrial dysfunction), which collectively impair stress adaptability.

What are the implications of the main findings?
The findings advocate for a paradigm shift towards early, pre-symptomatic (prodromal) therapeutic intervention, aiming to modulate the HSPB1 interactome and remodel neural homeostasis to forestall degeneration.They underscore the necessity for precision medicine strategies that target the underlying maladaptive stress response, moving beyond symptomatic management to achieve true neuroprotection in CMT.

The findings advocate for a paradigm shift towards early, pre-symptomatic (prodromal) therapeutic intervention, aiming to modulate the HSPB1 interactome and remodel neural homeostasis to forestall degeneration.

They underscore the necessity for precision medicine strategies that target the underlying maladaptive stress response, moving beyond symptomatic management to achieve true neuroprotection in CMT.

Charcot–Marie–Tooth (CMT) disease represents the most prevalent inherited peripheral neuropathy with a broad range of clinical manifestations, inheritance patterns, and causative genes. The primary pathological hallmark is progressive degeneration, predominantly affecting sensory and motor neurons, leading to prominent sensory deficits and progressive motor impairments. While neuropathy-causing mutations in the ubiquitously expressed small heat shock protein HSPB1 account for a subset of axonal CMT cases, the mechanisms underlying the selective vulnerability of peripheral neurons remain poorly understood. In this review, we synthesize emerging evidence to reframe HSPB1-related CMT as a prototypical gene–environment interaction disorder. The unique anatomical exposure and high metabolic demands of the peripheral nervous system (PNS) render it particularly vulnerable to HSPB1 mutation-mediated homeostatic collapse, which manifests through three interconnected pathological axes: proteostatic disturbance, cytoskeletal dysregulation, and mitochondrial dysfunction. Crucially, these deficits converge to impair the stress adaptability of peripheral neurons, creating a maladaptive feedback loop wherein environmental stressors exacerbate intrinsic vulnerabilities. We further propose a phase-specific therapeutic framework that prioritizes early intervention during the clinically silent yet biologically active prodromal stage, when targeted modulation of the HSPB1 chaperone interactome and remodeling neural homeostasis may forestall neurodegeneration. This therapeutic paradigm shift from symptomatic management to preclinical neuroprotection underscores the imperative for precision medicine approaches in future CMT intervention.