MFM13 Library

Wannarong et al. (2025) performed a natural history study of myofibrillar myopathies (MFM) and MFM-related genetic disorders using the Mayo Clinic Clinical Database (1993–2024), including 80 patients (46 males, 34 females) with either pathologically confirmed MFM or myopathies linked to MFM-associated genes. The study aimed to better characterize how these conditions present and progress in real-world clinical settings. Among the cohort, only one patient carried an HSPB8 mutation, which at the time was classified among hereditary myopathies “other than MFM.” Data collection ended in March 2024, prior to the formal reclassification of HSPB8 as MFM13 (OMIM #621078 in 2025). Importantly, the reported HSPB8 case showed myofibrillar pathology. Overall, the study highlights marked clinical variability across MFM-related disorders, with desminopathy emerging as a more severe subtype characterized by earlier cardiac and respiratory involvement and faster progression requiring mobility support. The findings underscore the importance of early genetic diagnosis and multidisciplinary care in MFM-spectrum diseases, including HSPB8-associated myopathy (MFM13).

The 2026 review by Zhou et al. is the first comprehensive overview of MFM13, providing an in-depth analysis of HSPB8 biology and its role within the CASA complex. The authors examine pathogenic HSPB8 mutations, with a particular focus on frameshift variants associated with MFM13, comparing how different mutations influence disease severity. The review highlights three key pathogenic mechanisms: a toxic gain of function driven by protein aggregation, a dominant-negative effect on wild-type HSPB8 and CASA complex activity, and the still-debated contribution of haploinsufficiency. It also draws attention to emerging and underexplored roles of HSPB8 in mitochondrial homeostasis, stress granule dynamics, and the Integrated Stress Response. In addition, the authors summarize clinical outcomes in MFM13 patients and discuss potential therapeutic strategies.

The 2026 study by Piccolella et al., focuses on exmination breast cancer from the perspective of autophagy, emphasizing that this cellular “self-cleaning” process plays a complex role in cancer. In early stages, autophagy can help prevent tumor development by removing damaged proteins and organelles. However, in advanced stages, the same process may support cancer cell survival under stress, thereby promoting disease progression.It has been shown that HSPB8 is expressed in estrogen receptor–positive (ER+) breast cancer. Under stress conditions, its overexpression enhances autophagy, as well as cancer cell growth, movement, and survival. BAG3 is also highly expressed in breast cancer cells, and its elevated levels are associated with poorer patient prognosis. The authors studied how HSPB8 and BAG3 influence the ability of breast cancer cells to spread (metastasis). They focused on protein tyrosine kinase 2 (PTK2), also known as FAK, a protein that acts like a central “switch” inside cells, activating pathways (such as PI3K, AKT, and MAPK) that control cell growth, movement, and survival. They found that when HSPB8 levels were reduced, the active (phosphorylated) form of FAK also decreased. As a result, breast cancer cells (MCF-7 and T47D, both estrogen receptor–positive lines) showed lower ability to grow, move, and attach, key features needed for metastasis. In addition, experiments demonstrated that BAG3 physically associates and co-localizes with FAK in breast cancer tissue, supporting a functional link between these proteins in regulating tumor cell behavior.

"The 2025 study by Ziemian et al., explores how myopathies and muscular dystrophies develop at the molecular level and how this knowledge can improve diagnosis and treatment. The authors highlight key genetic and cellular mechanisms behind muscle degeneration and emphasize the need for integrative approaches combining advanced diagnostics with emerging therapies. The study also highlights HSPB8, a small heat shock protein that plays a crucial role in protein quality control in muscle cells. When HSPB8 function is impaired, toxic protein aggregates can build up, contributing to muscle weakness diseases such as certain myopathies (MFM13) and motor neuron disorders. The paper also points toward the future, where precision medicine, gene-based therapies, and novel biomarkers could transform patient care and outcomes."

The review by Inoue et al. addresses the confusion around the definition of myofibrillar myopathies (MFM) by proposing a clearer, mechanism-based classification. The authors suggest defining MFM as a “Z-disk-opathy,” emphasizing that the disease primarily originates from defects at the Z-disk of the muscle fiber. The review explains that true MFMs are caused by disruptions in Z-disk proteins or their proper maintenance (proteostasis), while some other myopathies only show MFM-like pathological features but arise from different molecular mechanisms. Key points include the fact that many MFM-causing mutations are dominant and affect structural Z-disk proteins, as well as the important role of chaperone dysfunction in disease development. Overall, the authors argue that defining MFM as a Z-disk-opathy provides a clearer framework for diagnosis and understanding disease mechanisms. This distinction is important for clinical practice, as it can improve diagnostic accuracy, and for research, as it supports the development of targeted therapies aimed at restoring Z-disk protein balance or reducing harmful protein accumulation

The Yu et al., study (2025) investigated the role of HSPB8 in type 2 diabetes mellitus (T2DM), with a particular focus on its impact on diabetic cardiomyopathy (DCM) in mice. Using transcriptomic analysis, the researchers demonstrated that HSPB8 expression is reduced in the cardiac tissue of DCM mice. In their earlier work, the authors showed that HSP22 alleviates vascular endothelial cell injury in T2DM mice by inhibiting oxidative stress and inflammatory responses. Building on these findings, their latest study suggests that oxidative stress and inflammation are closely linked to the development of DCM in mice. To further clarify the role of HSPB8 in DCM, the team generated HSPB8 knockout and HSPB8 overexpression mouse models. The results showed that HSPB8 overexpression alleviates DCM, whereas loss of HSPB8 aggravates disease progression. Mechanistically, HSPB8 was shown to reduce oxidative stress and inflammation, leading to improved cardiac outcomes.

The 2025 review take a deep dive into genes that can cause both myopathies and neuropathies, highlighting the growing genetic and clinical overlap between these conditions. Among the genes listed is HSPB8, known for its role in MFM13. The authors emphasize that this overlap has important diagnostic implications. Neuropathies and myopathies can share the same disease-causing genes, which may lead to different symptoms in different patients. "

The 2025 study by Putko et al., two new cases, one patient with a novel missense mutation (c.185G>A (p. Gly62Asp)) and the second one with a mutation previously described by Ghaoui et al, 2015 (c.421 A>G (p.Lys141Glu)). Patient 1 carries a novel missense mutation c.185G>A (p. Gly62Asp). The first symptoms appeared at the age of 10, characterized by leg weakness. By age 60, the patient presents with myopathy with rimmed vacuoles (upper-limb involvement) and dHMN. The authors suggested that while diabetes may have contributed to neuropathy, the long-standing leg weakness supports dHMN as the main etiology. Patient 2, in his late 30s, showed myopathy symptoms due to HSPB8, c.421 A>G (p.Lys141Glu), the mutation previously described by Ghaoui et al. in 2015. In case of patient 2 authors highlight the presence of TIA1 aggregates*, but note the absence of Z-disk myofibrillar aggregates, which are typically seen in classic myofibrillar myopathies. However, they suggested that the absence of Z-disk myofibrillar aggregates should not exclude an HSPB8-related neuromuscular disorder.s.

The 2025 study by Fu et al., published in Frontiers in Genetics, identifies HSPB8 as a potential tumor suppressor and therapeutic target in prostate cancer. Using bioinformatic and experimental approaches, the authors found that HSPB8 expression is significantly reduced in prostate cancer tissues compared to normal samples. Low HSPB8 levels were linked to poorer patient survival and higher tumor aggressiveness. Functional studies showed that HSPB8 silencing increased proliferation, invasion, and migration of prostate cancer cells through activation of the PI3K–AKT–mTOR signaling pathway. The findings suggest that restoring HSPB8 activity could help inhibit prostate cancer progression and improve prognosis.

The 2025 study by Chen et al. investigates the role of HSPB8 and other key genes in gallbladder cancer using a multi-omics integrated approach. Analyzing transcriptomic and single-cell RNA sequencing data, the authors identified six genes (CTSG, FLNC, CCNB1, HSPB8, NR4A1, and MYLK) associated with the formation of tertiary lymphoid structures (TLS)-immune cell clusters linked to better cancer prognosis. Among them, HSPB8 showed significant involvement in immune infiltration, tumor suppression, and patient survival. These findings expand the understanding of HSPB8’s function beyond autophagy and muscle maintenance, suggesting it also contributes to immune regulation and tumor biology.

The 2025 study by Du et al., uncovers how ZNF33B promotes Japanese encephalitis virus (JEV) replication by regulating post-translational modification of the viral nonstructural protein 5 (NS5). The authors show that ZNF33B binds viral RNA to stabilize it and translocates from the nucleus to the cytoplasm during infection. Mechanistically, ZNF33B enhances SUMOylation of NS5 at lysine 269 and 846 by recruiting HSPB1 and HSPB8, which act as SUMO E3 ligases. This modification prevents NS5 ubiquitination and degradation, ensuring viral polymerase stability and efficient replication. The findings reveal a new mechanism by which JEV exploits host proteins-particularly ZNF33B and HSPB8-to sustain infection and identify potential antiviral targets within the SUMOylation pathway.

The 2025 study by Montepietra et al. explores how the K141E mutation in HSPB8 affects protein behavior. Using single-molecule FRET and simulations, the authors show that K141E makes the protein more flexible and unstable, especially under normal salt conditions. This leads to more unfolded forms and likely reduces HSPB8’s ability to act as a chaperone. The findings suggest that even a single amino acid change can disturb protein structure and contribute to neuromuscular disease by weakening the protein’s protective function.

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.

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.

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).

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.

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).

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

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^K141N/K141N) developed progressive motor deficits, peripheral axonopathy, and skeletal muscle pathology characterized by Z-disk disorganization and protein aggregation involving HSPB8, β-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.

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.

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.

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).

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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 like, 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.

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.

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 that 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.

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.

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.

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.

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.

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.

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.

The 2025 study by Montepietra et al. explores how the K141E mutation in HSPB8 affects protein behavior. Using single-molecule FRET and simulations, the authors show that K141E makes the protein more flexible and unstable, especially under normal salt conditions. This leads to more unfolded forms and likely reduces HSPB8’s ability to act as a chaperone. The findings suggest that even a single amino acid change can disturb protein structure and contribute to neuromuscular disease by weakening the protein’s protective function.

The 2025 study by Montepietra et al. explores how the K141E mutation in HSPB8 affects protein behavior. Using single-molecule FRET and simulations, the authors show that K141E makes the protein more flexible and unstable, especially under normal salt conditions. This leads to more unfolded forms and likely reduces HSPB8’s ability to act as a chaperone. The findings suggest that even a single amino acid change can disturb protein structure and contribute to neuromuscular disease by weakening the protein’s protective function.