Summary of a recently published review on HSPB8 Associated Neuromuscular Disorders
A recent article published on March 23, 2025, in the International Journal of Molecular Sciences —"The Spectrum of Small Heat Shock Protein B8 (HSPB8)-Associated Neuromuscular Disorders”, by Rashed HR, Nath SR, and Milone M., from the Department of Neurology, Mayo Clinic in Rochester, US, in collaboration with the Department of Neurology, Ain Shams University in Cairo, Egypt — is the only review to date focused solely on disorders caused by mutations in HSPB8 gene.
This article is a valuable resource for researchers, clinicians, and families affected by HSPB8-related disorders. It brings together current knowledge on how this small heat shock protein works, how its mutations disrupt neuromuscular health, and what strategies are being explored to treat these rare but serious diseases.
Below, we summarize the key findings of this review. For the full article, click here.
🔬 What is HSPB8 and Why Is It Important?
HSPB8 is a small heat shock protein critical for maintaining protein homeostasis. It works with partners like BAG3 and HSP70 in the CASA complex to identify and clear misfolded proteins via autophagy, a type of cellular self-cleaning process.
It’s especially important in muscle, heart, and nerve cells, where protein quality control is vital for function and survival.
🧬 How Do HSPB8 Mutations Cause Disease?
Mutations in HSPB8 are linked to several dominantly inherited neuromuscular disorders (Figure 1). Mutations causing MFM13, or HSPB8 Myopathy, are depicted in green.
Figure 1. From Rashed et al, 2025. Schematic representation of HSPB8, protein domains, and mutations causing neuromuscular diseases. p.P90L, p.N138T, and p.K141M have been associated with dHMN; p.K141T has been associated with CMT2L; p.K141N has been associated with dHMN and CMT2L; p.K141E has been reported in neuromyopathy. p.Q170Gfs*45, p.P173Sfs*43, p.T176Wfs*38, p.T194Sfs*23, and p.G192Afs*55 in CTD have been associated with myopathy; p.P173Sfs*43 has been associated with neuromyopathy.
The mutation can cause specific neuropathies and motor dysfunctions such as (Figure 1 and Table 1)
Distal Hereditary Motor Neuropathy (dHMN) is associated with missense mutations in the N-terminal or α-crystallin domain of HSPB8. These mutations lead to progressive motor nerve degeneration, causing distal muscle weakness and atrophy, primarily in the lower limbs (OMIM: 158590).
Charcot–Marie–Tooth Disease Type 2L (CMT2L) is linked especially to mutations at Lys141 in HSPB8, such as K141N and K141E. This condition results in motor and mild sensory axonal neuropathy, characterized by distal muscle weakness, sensory loss, and gait abnormalities (OMIM: 608673).
Myofibrillar Myopathy 13 with Rimmed Vacuoles (MFM13) or HSPB8 Myopathy is caused by frameshift or truncation mutations in the C-terminal domain of HSPB8. It leads to toxic protein aggregation, impaired autophagy, and muscle fiber damage, manifesting as progressive muscle weakness and myopathy symptoms (OMIM: 621078).
Some of mutations result in mixed phenotypes that include both neuropathic and myopathic symptoms (Figure 1)
Table 1 From Rashed et al, 2025. Clinical Features of HSPB8-associated neuromuscular disorders. dHMN: distal hereditary motor neuropathy; CMT2L: Charcot–Marie–Tooth type 2L; Myopathy: HSPB8 Myopathy = MFM13: Myofibrillar Myopathy 13 with Rimmed Vacuoles
🧪 Insights from Cell and Animal Models
Cell and animal models have helped unravel how mutant HSPB8 disrupts protein clearance:
Cell models show that mutations lead to aggregate formation and impaired autophagy.
Mouse models carrying HSPB8 mutations develop motor neurons and muscle pathology, similar to patients.
Drosophila (fruit fly) models reveal structural muscle defects and mitochondrial dysfunction.
These findings support a toxic gain-of-function mechanism: instead of losing function, the mutated HSPB8 becomes harmful by forming aggregates and overwhelming the cellular cleanup machinery.
💊 Therapeutic Avenues on the Horizon
Although there is no approved therapy yet, the review outlines several experimental strategies:
Enhancing autophagy with small molecules (e.g., trehalose, piplartine)
Increasing HSPB8 expression using drugs like colchicine or doxorubicin
Gene and protein therapy, including delivery via viral vectors or extracellular vesicles
RNA interference, though this approach has shown limited success so far
All these aims to restore balance to the cell’s protein quality control system.
⚠️ Challenges and Knowledge Gaps
The review also highlights important limitations in current research:
Phenotypic variability is still not fully understood, due to the rarity of HSPB8 mutations.
Existing models may not fully capture the complexity of human disease.
Modifier genes and environmental factors could play a role in disease onset and severity, but more data are needed.
These gaps must be addressed to enable better therapies and diagnostic tools.
✅ Why This Review Matters
This review is a milestone for the HSPB8 research and patient community. It pulls together years of research and offers a roadmap for where we need to go next—from deeper understanding to real-world therapies.
We encourage everyone in the HSPB8 community to read it, share it, and discuss it. The full article is open access and available here:
Podcast: Episode 3