MFM13 Library

Original
ZNF33B facilitates Japanese encephalitis virus replication by controlling HSPB1/8-mediated SUMOylation of nonstructural protein 5
Year:
2025
Journal:
Journal of Virology
Summary
Original
NMR Insights Into Stress-Induced Modulation of the Monomer–Dimer Equilibrium in a Small Heat Shock Protein
Year:
2025
Journal:
Magnetic Resonance in Chemistry
Summary
Original
H11 Kinase/Heat Shock Protein 22 Deletion Impairs Both Nuclear and Mitochondrial Functions of STAT3 and Accelerates the Transition Into Heart Failure on Cardiac Overload
Year:
2011
Journal:
Heart Failure
Summary
This 2011 study by Qiu et al. shows that deletion of Hsp22 (also known as H11 kinase) in mice accelerates heart failure under pressure overload. The knockout mice had impaired activation of the transcription factor STAT3 in both the nucleus and mitochondria, leading to reduced gene expression, mitochondrial respiration, and cardioprotective signaling. These defects resulted in faster progression to cardiac dysfunction and increased mortality. The study identifies Hsp22 as a previously unrecognized regulator of STAT3-driven stress responses and mitochondrial function in the heart.
Original
The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS)
Year:
2010
Journal:
Human Molecular Genetcs
Summary
This 2010 study by Crippa et al. investigates the role of the small heat shock protein B8 (HSPB8) in amyotrophic lateral sclerosis (ALS). Using both in vitro (NSC34 motor neuron cells) and in vivo (G93A-SOD1 transgenic mice) ALS models, the authors demonstrate that HSPB8 is upregulated in response to proteasome impairment and misfolded mutant SOD1 accumulation. HSPB8 facilitates the clearance of these toxic proteins through autophagy, independently of the proteasome, by forming a complex with BAG3, Hsc70, and CHIP. The study also shows that HSPB8 promotes degradation of truncated, aggregation-prone TDP-43, another ALS-linked protein. These findings suggest that enhancing HSPB8 expression may be a promising therapeutic strategy for both familial and sporadic ALS.
Case Study
Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy
Year:
2016
Journal:
Neurology Journal
Summary
The 2016 study by Ghaoui et al. reports two families carrying heterozygous HSPB8 mutations—c.421A>G (p.K141E) and c.151insC (p.P173Sfs*43)—presenting with a combined phenotype of distal myopathy and motor neuropathy. Clinical features included early-onset foot drop, distal lower limb weakness, and progressive proximal involvement. Muscle biopsies showed myofibrillar pathology with rimmed vacuoles, desmin-positive protein aggregates, and markers of autophagy including p62, LC3b, and TDP-43. Nerve conduction studies confirmed a length-dependent axonal motor neuropathy, while MRI revealed both early neurogenic and later dystrophic changes. Functional studies demonstrated reduced chaperone activity of mutant HSPB8, implicating CASA complex dysfunction in disease pathogenesis. This was the first report to link HSPB8 mutations with dual neuromuscular involvement and expands the known spectrum of MFM13 (OMIM, 621078).
Original
Transcriptional induction of the heat shock protein B8 mediates the clearance of misfolded proteins responsible for motor neuron diseases
Year:
2016
Journal:
Scientific Reports
Summary
This 2016 study by Crippa et al. demonstrates that transcriptional induction of HSPB8 promotes the autophagic clearance of misfolded proteins associated with motor neuron diseases (MNDs), such as ALS and SBMA. The authors show that HSPB8, together with BAG3 and the HSP70/CHIP complex, enhances degradation of toxic TDP-43 and its aggregation-prone C-terminal fragment TDP-25, even in sporadic ALS cases. A high-throughput screening identified colchicine and doxorubicin as effective HSPB8 inducers. These compounds also increased TFEB, p62/SQSTM1, and LC3 expression, reduced TDP-25 aggregation, and improved proteostasis without triggering heat shock responses. This work identifies HSPB8 as a therapeutic target and supports autophagy modulation as a strategy to treat protein misfolding disorders.
Case Study
HSPB8 haploinsufficiency causes dominant adult?onset axial and distal myopathy
Year:
2017
Journal:
Acta Neuropathologica
Summary
The 2017 study by Echaniz-Laguna et al. reports a heterozygous HSPB8 frameshift mutation, c.508_509delCA (p.Gln170Glyfs*45), in five patients from three unrelated families presenting with adult-onset axial and distal myopathy. The disease began with camptocormia around age 39, followed by foot drop and progressive limb weakness. Muscle biopsies revealed dystrophic changes, rimmed vacuoles, and protein aggregates positive for desmin, ubiquitin, and TDP-43, consistent with myofibrillar myopathy. MRI showed severe fatty infiltration, especially in paraspinal muscles. Functional studies demonstrated a ~60% reduction in HSPB8 protein expression, with no evidence of elongated or truncated forms, indicating haploinsufficiency due to nonsense-mediated decay. This was the first study to demonstrate that HSPB8 mutations can cause a pure myopathy without neuropathy, expanding the phenotypic spectrum of MFM13 (OMIM, 621078).
Case Study
Altered TDP-43-dependentsplicingin HSPB8-related distal hereditary motor neuropathy and myofibrillar myopathy
Year:
2017
Journal:
European Journal of Neurology
Summary
The 2017 study by Cortese et al. describes a family—including triplets—carrying a heterozygous HSPB8 missense mutation (K141E) presenting in their 20s–30s with a mixed neuromuscular disorder marked by distal hereditary motor neuropathy (dHMN) and myofibrillar myopathy (MFM). Clinically, affected members had progressive distal and proximal lower limb weakness with truncal muscle involvement, mild CK elevation, and motor axonal neuropathy on nerve conduction. Muscle MRI showed a selective pattern of muscle damage, while biopsy revealed rimmed vacuoles and protein aggregates. Importantly, the study demonstrated altered RNA metabolism: muscle tissue exhibited reduced TDP‑43 mRNA levels and disrupted splicing of TDP‑43 target transcripts (POLDIP3, FNIP1, BRD8), implicating TDP‑43 loss-of-function as a downstream pathogenic mechanism of HSPB8 mutation
Original
A knock‑in/knock‑out mouse model of HSPB8‑associated distal hereditary motor neuropathy and myopathy reveals toxic gain‑of‑function of mutant Hspb8
Year:
2017
Journal:
Acta Neuropathologica
Summary
This 2019 study by Bouhy et al. describes a knock-in/knock-out mouse model of HSPB8-associated distal hereditary motor neuropathy (dHMN) and distal myopathy, harboring the patient-derived K141N mutation. Homozygous knock-in mice (Hspb8<sup>K141N/K141N</sup>) developed progressive motor deficits, peripheral axonopathy, and skeletal muscle pathology characterized by Z-disk disorganization and protein aggregation involving HSPB8, ?B-crystallin, and desmin. These aggregates were associated with impaired autophagic clearance, pointing to a disruption of chaperone-assisted selective autophagy (CASA). In contrast, Hspb8 knock-out mice showed no overt motor phenotype, suggesting a toxic gain-of-function mechanism rather than loss of function. This study provides in vivo validation that mutant HSPB8 impairs proteostasis via CASA dysfunction and highlights autophagy impairment as a key contributor to HSPB8-linked neuromyopathies.
Review
The Role of the Heat Shock Protein B8 (HSPB8) in Motoneuron Diseases
Year:
2017
Journal:
Frontiers in Molecular Neuroscience
Summary
This 2017 review by Rusmini et al. explores the role of HSPB8 in clearing misfolded proteins via chaperone-assisted selective autophagy (CASA) in motoneuron diseases like ALS and SBMA. HSPB8—upregulated in motoneurons and muscle during disease—partners with BAG3 and HSP70 to reroute toxic aggregates to autophagy, relieving stress on the proteasome. The authors highlight therapeutic strategies to pharmacologically induce HSPB8 (e.g., trehalose, colchicine) and suggest that enhancing HSPB8-BAG3 function may help preserve proteostasis and delay disease progression.
Clinical Trials
Improved mobility with metformin in patients with myotonic dystrophy type 1 a randomized controlled trial
Year:
2018
Journal:
Brain
Summary
This phase II double-blind, placebo-controlled trial by Bassez et al. evaluated the effect of metformin on ambulation in adults with DM1. In the per-protocol population, metformin significantly improved walking distance in the 6-minute walk test (+29.2 m vs. placebo) and enhanced gait mechanical power. However, effects on myotonia and muscle strength were minimal, and gastrointestinal side effects were frequent. Despite limitations in sample size and dropout rates, the results support further investigation of metformin in larger phase III trials as a potential mobility enhancer in DM1.
Case Study
New family with HSPB8-associated autosomal dominant rimmed vacuolar myopathy
Year:
2019
Journal:
Neurology Genetics
Summary
The 2019 study by Al-Tahan et al. describes a multigenerational family affected by autosomal dominant rimmed vacuolar myopathy caused by a novel HSPB8 frameshift mutation, c.515dupC (p.Pro173Serfs*43). Affected individuals presented with adult-onset distal lower limb weakness progressing proximally, along with prominent endomysial fibrosis, rimmed vacuoles, and desmin-positive protein aggregates on muscle biopsy. MRI showed selective fatty degeneration of lower limb muscles. Functional studies in patient-derived fibroblasts revealed significantly reduced HSPB8 expression and impaired autophagy, indicated by increased LC3 and p62 levels. This study provided the first in vitro functional confirmation of this mutation's pathogenicity and highlighted the central role of impaired chaperone-assisted selective autophagy in MFM13 (OMIM, 621078).
Review
The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death
Year:
2019
Journal:
Frontiers of Neuroscience
Summary
This 2019 review by Cristofani highlights HSPB8’s central role in the chaperone-assisted selective autophagy (CASA) complex, crucial for degrading misfolded, aggregation-prone proteins in neurodegenerative and neuromuscular diseases. The authors describe HSPB8’s protective action in ALS, SBMA, and other proteinopathies, emphasizing its cooperation with BAG3 and HSP70 in facilitating autophagic clearance. They also discuss pharmacological upregulation of HSPB8 as a promising therapeutic approach.
Review
Small heat shock proteins in neurodegenerative diseases
Year:
2020
Journal:
Cell Stress and Chaperones
Summary
This 2020 review by Vendredy et al., explores how mutations in sHSPs (HSPB1, HSPB3, HSPB8) underlie inherited peripheral neuropathies like CMT2 and dHMN, and how sHSPs also protect against protein aggregation in CNS disorders (e.g., Alzheimer’s, Parkinson’s, Huntington’s, and ALS). The paper delves into sHSP structure, oligomerization, and chaperone mechanisms, emphasizing their ATP‑independent holdase activity. It highlights sHSP interactions with disease‑associated aggregating proteins—Aβ, tau, α‑synuclein, huntingtin, TDP‑43, and SOD1—and discusses their potential as modifiers and therapeutic targets
Review
Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results
Year:
2020
Journal:
International Journal of Molecular Sciences
Summary
This 2020 review by Sarparanta et al. examines how mutations in molecular chaperones and co-chaperones—such as DNAJB6, DNAJB2, HSPB1, HSPB3, HSPB5 (CRYAB), HSPB8, and BAG3—lead to neuromuscular diseases. The authors describe diverse pathogenic mechanisms, including toxic gain-of-function, impaired protein quality control (PQC), and disrupted stress granule dynamics. They also present new findings showing that the BAG3 p.P209L mutation alters DNAJB6 turnover and localization. The review highlights shared pathways among chaperonopathies and emphasizes the role of phase separation and prion-like domains in muscle and multisystem proteinopathies.
Case Study
A novel heterozygous mutation in the C-terminal region of HSPB8 leads to limb-girdle rimmed vacuolar myopathy
Year:
2020
Journal:
Neuromuscular Disorder
Summary
This 2020 case report by NicolauS. et al., describes a patient with a de novo heterozygous HSPB8 mutation, c.577_580dupGTCA (p.Thr194Serfs*23), which causes substitution of the last three amino acids and addition of 19 extra residues at the C-terminal end of the protein. This unique alteration leads to a distinct clinical presentation: symptoms began at age 19 with progressive proximal lower limb weakness, scapular winging, neck contracture, and lumbar lordosis. Muscle biopsy confirmed rimmed vacuoles and protein aggregates typical of rimmed vacuolar myopathy (RVM). Notably, this patient showed no respiratory failure or cardiac involvement, consistent with the rarity of such symptoms in HSPB8-related myopathies. This case expands the phenotypic spectrum and highlights the importance of considering de novo mutations that leads to MFM13 (OMIM, 621078) in sporadic limb-girdle weakness.
Review
The Role of HSPB8, a Component of the Chaperone-Assisted Selective Autophagy Machinery, in Cancer
Year:
2021
Journal:
Cells
Summary
This 2021 review by Cristofani et al. explores the diverse and context-dependent roles of HSPB8 in cancer. While HSPB8 often promotes cell survival by facilitating the clearance of misfolded proteins via autophagy, it can also act as a tumor suppressor in certain contexts. The authors describe how HSPB8 influences processes like apoptosis, cell proliferation, migration, and response to therapy, with its impact varying by cancer type. The review emphasizes the need for caution in targeting HSPB8 therapeutically, as its functions can be either protective or harmful depending on the tumor environment.
Case Study
A novel deletion in the C-terminal region of HSPB8 in a family with rimmed vacuolar myopathy
Year:
2021
Journal:
Journal of Human Genetics
Summary
The 2021 study by Inoue-Shibui et al., identified a novel heterozygous frameshift variant, c.525_529del, in the HSPB8 gene in a large Japanese family with rimmed vacuolar myopathy (RVM), now called Myofibrillar Myopathy 13 with Rimmed Vacuoles (OMIM, 621078). This mutation causes the HSPB8 protein to have an unusually long tail at its end (the C-terminal end). This extended part includes an isoleucine–leucine–valine (ILV) sequence, which acts like a sticky patch that helps proteins clump together into larger structures. This process, called oligomerization, is typical for small heat shock proteins, but in this case, it may lead to excessive or harmful buildup. In silico analyses suggest the altered protein has low solubility and a high tendency to aggregate. Clinically, the affected individuals showed severe respiratory failure—previously unreported in HSPB8 mutations—along with progressive muscle weakness, severe fat replacement, and muscle atrophy, especially in the paraspinal muscles.
Review
Distal hereditary motor neuropathies
Year:
2022
Journal:
Revue Neurologique
Summary
FALSE
Review
The role of autophagy-lysosomal pathway in motor neuron diseases
Year:
2022
Journal:
Biochemical Society Transactions
Summary
This 2022 review by Tedesco et al. examines the role of the autophagy-lysosomal pathway (ALP) in motor neuron diseases (MNDs). The authors explain how defects in ALP-related genes or protein aggregation stress can impair autophagy, leading to neurodegeneration. They highlight the importance of chaperone-assisted selective autophagy (CASA), especially the HSPB8–BAG3 complex, in targeting misfolded proteins for degradation. The review also discusses therapeutic strategies, including ALP activators like trehalose and colchicine, which promote HSPB8 expression and improve protein clearance. These findings support ALP modulation as a promising avenue for MND treatment.
Review
Insights on Human Small Heat Shock Proteins and Their Alterations in Diseases
Year:
2022
Journal:
Frontiers in Molecular Biosciences
Summary
This 2022 review by Tedesco et al. provides a broad overview of human small heat shock proteins (sHSPs), covering their structure, expression patterns, and roles in cellular stress responses. The authors describe how sHSPs like HSPB1, HSPB5, and HSPB8 contribute to proteostasis, cytoskeletal integrity, and organelle function. They also discuss how mutations in sHSP genes lead to various diseases, including myopathies, neuropathies, and cataracts. The review emphasizes the potential of targeting sHSPs for therapeutic development in protein misfolding and aggregation disorders.
Review
The Role of Small Heat Shock Proteins in Protein Misfolding Associated Motoneuron Diseases
Year:
2022
Journal:
International Journal of Molecular Sciences
Summary
This 2022 review by Tedesco et al. focuses on the roles of small heat shock proteins (sHSPs), especially HSPB8, in motor neuron diseases (MNDs). The authors describe how sHSPs maintain proteostasis by recognizing and clearing misfolded proteins via chaperone-assisted selective autophagy (CASA). Mutations in HSPB1 and HSPB8 disrupt this process, leading to toxic aggregate accumulation in diseases like ALS and distal hereditary motor neuropathy. The review also highlights sHSPs as promising therapeutic targets, with potential strategies including pharmacological upregulation and gene-based interventions.
Review
Role of Chaperone-Mediated Autophagy in Ageing Biology and Rejuvenation of Stem Cells
Year:
2022
Journal:
Frontiers in Cell and Developmental Biology
Summary
This 2022 review by Vitale et al. discusses the role of chaperone-mediated autophagy (CMA) in aging and stem cell biology. The authors describe how CMA selectively degrades damaged or unnecessary proteins to maintain proteostasis and how its decline with age contributes to cellular dysfunction. In stem cells, CMA supports self-renewal and differentiation by regulating metabolism, stress responses, and epigenetic factors. The review also highlights recent strategies aimed at rejuvenating stem cells through CMA activation, positioning CMA as a promising therapeutic target for aging and regenerative medicine.
Original
HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies
Year:
2023
Journal:
Autophagy
Summary
This 2022 review by Tedesco et al. examines the role of the autophagy-lysosomal pathway (ALP) in motor neuron diseases (MNDs). The authors explain how defects in ALP-related genes or protein aggregation stress can impair autophagy, leading to neurodegeneration. They highlight the importance of chaperone-assisted selective autophagy (CASA), especially the HSPB8–BAG3 complex, in targeting misfolded proteins for degradation. The review also discusses therapeutic strategies, including ALP activators like trehalose and colchicine, which promote HSPB8 expression and improve protein clearance. These findings support ALP modulation as a promising avenue for MND treatment.
Review
Multisystem proteinopathies (MSPs) and MSP-like disorders: Clinical-pathological-molecular spectrum
Year:
2023
Journal:
Annals of Clinical and Translational Neurology
Summary
The 2023 study by Chompoopong et al., explores how reduced functional brain network flexibility contributes to cognitive deficits in patients with temporal lobe epilepsy (TLE). Using verbal fluency tasks and fMRI, the study found that individuals with TLE show impaired ability to reconfigure brain network connections during cognitive challenges, which likely underlies their observed cognitive impairments
Review
The chaperone-assisted selective autophagy complex dynamics and dysfunctions
Year:
2023
Journal:
Autophagy
Summary
This 2022 review by Tedesco et al. examines the role of the autophagy-lysosomal pathway (ALP) in motor neuron diseases (MNDs). The authors explain how defects in ALP-related genes or protein aggregation stress can impair autophagy, leading to neurodegeneration. They highlight the importance of chaperone-assisted selective autophagy (CASA), especially the HSPB8–BAG3 complex, in targeting misfolded proteins for degradation. The review also discusses therapeutic strategies, including ALP activators like trehalose and colchicine, which promote HSPB8 expression and improve protein clearance. These findings support ALP modulation as a promising avenue for MND treatment.
Original
Identification of HSPB8 modulators counteracting misfolded protein accumulation in neurodegenerative diseases
Year:
2023
Journal:
Life Sciences
Summary
This 2023 study by Chierichetti et al. identifies small molecules that enhance HSPB8 expression to counteract protein aggregation in neurodegenerative diseases. Using a cell-based screening approach, the authors found several FDA-approved drugs—including tretinoin and 4-phenylbutyric acid—that upregulate HSPB8 and reduce accumulation of misfolded mutant proteins like SOD1 and BAG3. These findings support pharmacological HSPB8 induction as a promising therapeutic strategy for proteotoxic conditions such as ALS and myopathies.
Review
The beauty and complexity of the small heat shock proteins: a report on the proceedings of the fourth workshop on small heat shock proteins
Year:
2023
Journal:
Cell Stress and Chaperones
Summary
This 2023 report by Ecroyd et al. summarizes presentations from the fourth international workshop on small heat shock proteins (sHSPs). Covering topics from structural dynamics to disease relevance, the report highlights advances in understanding sHSP oligomerization, client interactions, and roles in protein aggregation and phase separation. Special focus is given to disease-linked sHSP mutations, such as those in HSPB8 and HSPB1, their impact on autophagy and neurodegeneration, and therapeutic strategies including small molecules and gene therapy. The report reflects the growing importance of sHSPs in proteostasis and pathology.
Original
HSPB8 up-regulation alleviates cognitive dysfunction in a mouse model of sepsis-associated encephalopathy
Year:
2023
Journal:
International Immunopharmacology
Summary
This 2023 study by Ling et al. demonstrates that HSPB8 overexpression alleviates cognitive impairment in a mouse model of sepsis-associated encephalopathy (SAE). Using LPS-induced SAE models, the authors show that HSPB8 upregulation improves memory, reduces synaptic and neuronal damage, and protects mitochondrial function via the NRF1/TFAM pathway. HSPB8 also modulates DRP1-mediated mitochondrial fission and suppresses neuroinflammation by reducing IBA1 and NLRP3 activation. These findings highlight HSPB8 as a potential therapeutic target for SAE-related cognitive decline.
Original
Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches
Year:
2024
Journal:
Disease Model & Mechanisms
Summary
This 2024 review by Findlay explores the complexity of dominantly inherited muscle disorders, focusing on how mutant and wild-type alleles co-expressed in the same cells complicate treatment. The paper outlines key pathogenic mechanisms—haploinsufficiency, dominant-negative effects, and toxic gain-of-function—and discusses therapeutic strategies including allele-specific knockdown and knockdown-and-replace approaches. The review highlights promising advances in RNA- and virus-based therapies for dominant myopathies.
Review
Small heat shock protein B8: from cell functions to its involvement in diseases and potential therapeutic applications
Year:
2024
Journal:
Neural Regeneration research
Summary
This 2025 review by Chierichetti et al. provides a comprehensive overview of HSPB8’s cellular roles and its involvement in various diseases. The authors highlight HSPB8’s key function in chaperone-assisted selective autophagy (CASA) and its protective role in neurodegenerative and neuromuscular diseases by promoting clearance of misfolded proteins. HSPB8 also exhibits context-dependent effects in cancer and neuroinflammation. The review discusses emerging therapeutic strategies—including small molecules, viral vectors, and EV-based delivery—to modulate HSPB8 expression or function, emphasizing the need for cell- and tissue-specific targeting to minimize off-target effects.
Original
Autophagy induction by piplartine ameliorates axonal degeneration caused by mutant HSPB1 and HSPB8 in Charcot-Marie-Tooth type 2 neuropathies
Year:
2024
Journal:
Autophagy
Summary
This 2024 study by Sisto et al. explores the therapeutic potential of autophagy induction in motor neuron diseases caused by HSPB1 and HSPB8 mutations. Using patient-derived iPSC motor neurons and mutant mouse cells, the authors show that piplartine—a natural compound—restores autophagic activity, improves mitochondrial morphology, and reduces axonal degeneration and cellular stress. These findings suggest that targeting autophagy with small molecules like piplartine may be a promising strategy for treating CMT2 and other chaperonopathies.
Case Study
A novel c.515delC HSPB8-multisystem proteinopathy associated with inclusion body myopathy with cardiomyopathy
Year:
2024
Journal:
Pre-print
Summary
This 2024 preprint by Tan et al. describes a family with a novel HSPB8 frameshift mutation (c.515delC; p.Pro172Leufs*75) causing a multisystem proteinopathy that includes rimmed vacuolar myopathy, respiratory insufficiency, and cardiomyopathy. The mutation results in a toxic protein extension that likely disrupts the CASA complex. Male carriers showed earlier onset, more severe muscle weakness, and greater systemic involvement than females. The study expands the known clinical spectrum of HSPB8-related disorders, identifies codon 515 as a mutational hotspot, and supports the classification of HSPB8 diseases as multisystem proteinopathies.
Abstract
61P Characteristics of muscle computed tomography in a family with HSPB8-related rimmed vacuolar myopathy
Year:
2024
Journal:
Neuromuscular Disorders
Summary
FALSE
Case Study
Myofibrillar Myopathy: Clinico-Genetic Spectrum From a Neuromuscular Center in South India
Year:
2025
Journal:
Journal of Clinical Neuromuscular Disease
Summary
Oommenn et al., 2025 reported on 12 genetically confirmed patients with myofibrillar myopathy (MFM) in India. They found that DES mutations were the most common, but also identified cases involving HSPB8, FLNC, CRYAB, LDB3, and TTN. The HSPB8 mutation (c.566_567del) caused limb-girdle weakness with ptosis—a presentation not described before. This study expands the known clinical and genetic spectrum of MFM, especially in underrepresented populations.
Review
The Spectrum of Small Heat Shock Protein B8
(HSPB8)-Associated Neuromuscular Disorders
Year:
2025
Journal:
International Journal of Molecular Sciences
Summary
This 2025 review by Rashed et al. comprehensively outlines the clinical spectrum, genetic mutations, and molecular mechanisms of HSPB8-associated neuromuscular disorders. The authors detail how missense mutations typically cause distal hereditary motor neuropathy (dHMN) or Charcot–Marie–Tooth disease type 2L (CMT2L), while frameshift mutations in the C-terminal domain lead to myopathy with rimmed vacuoles and myofibrillar pathology. These frameshift variants disrupt chaperone-assisted selective autophagy (CASA) through toxic gain-of-function mechanisms. The review also discusses diagnostic features, disease models, and emerging therapies—including autophagy modulators, RNAi, and HSPB8 delivery—highlighting HSPB8 as a key player in neuromuscular disease and a potential therapeutic target.
Case Study
Expanding the spectrum of HSPB8-related myopathy: a novel mutation causing atypical pediatric-onset axial and limb-girdle involvement with autophagy abnormalities and molecular dynamics studies
Year:
2025
Journal:
Journal of Human Genetics
Summary
This 2024 study by Yang et al. reports a novel de novo HSPB8 frameshift mutation (p.Glu192Aspfs*55) causing an atypical, pediatric-onset axial and limb-girdle myopathy—the first such case described in the Chinese population. Muscle pathology revealed classic myofibrillar myopathy with inflammatory changes and autophagic vacuoles with sarcolemmal features (AVSF-like). Functional studies and molecular dynamics simulations showed that the elongated mutant HSPB8 protein is aggregation-prone, disrupts autophagy, and impairs chaperone activity via toxic gain-of-function mechanisms. These findings expand the genotype–phenotype spectrum of HSPB8-related myopathies and emphasize the role of autophagy dysregulation in disease pathogenesis.
Original
Small heat shock protein HSPB8 interacts with a pre-fibrillar TDP43 low complexity domain species to delay fibril formation
Year:
2025
Journal:
Pre-print
Summary
This 2025 preprint by Jami et al. shows that HSPB8 interacts with early, pre-fibrillar forms of the TDP‑43 low-complexity (LC) domain to delay its pathological aggregation. Using biophysical techniques like ThT assays, fluorescence polarization, FRAP, and crosslinking mass spectrometry, the study demonstrates that HSPB8 binds to early TDP-43 oligomers, specifically extending the nucleation phase of fibril formation. This interaction does not block fibril elongation but limits the maturation and rigidification of TDP-43 condensates. These findings highlight HSPB8’s unique ATP-independent chaperone activity and its potential to counteract pathological protein aggregation in neurodegenerative diseases.
Case Study
Novel HSPB8 mutations in severe early-onset myopathy with involvement of respiratory and cardiac muscles cause proteostasis defects in cell models
Year:
2025
Journal:
European Journal of Neurology
Summary
The 2025 study by Tedesco et al. describes three novel heterozygous HSPB8 frameshift mutations—p.P173Sfs*43, p.G192Afs*55, and p.T194Sfs*23—that lead to elongated C-terminal tails with a shared aberrant motif. Despite distinct genetic origins, all variants produced toxic protein aggregates, impaired autophagy, and disrupted CASA complex function. Muscle biopsies showed rimmed vacuoles, desmin, p62, and TDP-43 positivity. Importantly, this is the first functional validation of p.P173Sfs*43, confirming its pathogenicity. Clinically, patients presented with progressive weakness and frequent cardiac and respiratory involvement, indicating that these variants may define a more severe MFM13 phenotype driven by a toxic gain-of-function mechanism.
Original
Pathogenic Mechanism of the K141E Mutation in HSPB8: Insights from smFRET and Simulations
Year:
2025
Journal:
Cell Stress and Chaperones
Summary
The 2025 study by Tedesco et al. describes three novel heterozygous HSPB8 frameshift mutations—p.P173Sfs*43, p.G192Afs*55, and p.T194Sfs*23—that lead to elongated C-terminal tails with a shared aberrant motif. Despite distinct genetic origins, all variants produced toxic protein aggregates, impaired autophagy, and disrupted CASA complex function. Muscle biopsies showed rimmed vacuoles, desmin, p62, and TDP-43 positivity. Importantly, this is the first functional validation of p.P173Sfs*43, confirming its pathogenicity. Clinically, patients presented with progressive weakness and frequent cardiac and respiratory involvement, indicating that these variants may define a more severe MFM13 phenotype driven by a toxic gain-of-function mechanism.
Original
Interaction of small heat shock proteins with BAG3
Year:
2025
Journal:
Biochimie
Summary
The 2025 study by Tedesco et al. describes three novel heterozygous HSPB8 frameshift mutations—p.P173Sfs*43, p.G192Afs*55, and p.T194Sfs*23—that lead to elongated C-terminal tails with a shared aberrant motif. Despite distinct genetic origins, all variants produced toxic protein aggregates, impaired autophagy, and disrupted CASA complex function. Muscle biopsies showed rimmed vacuoles, desmin, p62, and TDP-43 positivity. Importantly, this is the first functional validation of p.P173Sfs*43, confirming its pathogenicity. Clinically, patients presented with progressive weakness and frequent cardiac and respiratory involvement, indicating that these variants may define a more severe MFM13 phenotype driven by a toxic gain-of-function mechanism.
