Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene

Rossor, Alexander M.; Morrow, Jasper M.; Polke, James M.; Murphy, Sinéad M.; Houlden, Henry; Inc-Rdcrc,; Laurá, Matilde; Manji, Hadi; Blake, Julian

doi:10.1016/j.nmd.2016.10.001

Cited by 31 publications

(51 citation statements)

References 16 publications

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“…Patients with HSPB1 mutations usually present with progressive weakness of the legs, with bilateral foot drop often arising as the first symptom. The age of onset is usually in the second decade of life, although onsets up to the seventh decade of life have also been reported (Harding and Thomas 1980;Capponi et al 2011;Echaniz-Laguna et al 2017a;Rossor et al 2017). Disease progression is slow and a significant percentage of patients develop upper limb weakness over the years, leading to loss of ambulation, resulting eventually in wheelchair dependence.…”

Section: Mutations In Shsps Causing Neurodegenerative Diseases Hspb1mentioning

confidence: 99%

“…Disease progression is slow and a significant percentage of patients develop upper limb weakness over the years, leading to loss of ambulation, resulting eventually in wheelchair dependence. Patients may also suffer from mild sensory involvement, although the degree of involvement is highly variable and can even differ between affected members of the same family (Rossor et al 2017). Other common features include mildly elevated creatine kinase levels, foot deformities, and thigh and hand weakness; and CNS involvement was observed in 5-10% of the patients (Echaniz-Laguna et al 2017a, Rossor et al 2017).…”

Section: Mutations In Shsps Causing Neurodegenerative Diseases Hspb1mentioning

confidence: 99%

“…Patients may also suffer from mild sensory involvement, although the degree of involvement is highly variable and can even differ between affected members of the same family (Rossor et al 2017). Other common features include mildly elevated creatine kinase levels, foot deformities, and thigh and hand weakness; and CNS involvement was observed in 5-10% of the patients (Echaniz-Laguna et al 2017a, Rossor et al 2017). So far, over 30 different mutations have been found in the HSPB1 gene leading to inherited peripheral neuropathies ( Fig.…”

Section: Mutations In Shsps Causing Neurodegenerative Diseases Hspb1mentioning

confidence: 99%

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Small heat shock proteins in neurodegenerative diseases

Vendredy

Adriaenssens

Timmerman

2020

Cell Stress and Chaperones

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Small heat shock proteins are ubiquitously expressed chaperones, yet mutations in some of them cause tissue-specific diseases.Here, we will discuss how small heat shock proteins give rise to neurodegenerative disorders themselves while we will also highlight how these proteins can fulfil protective functions in neurodegenerative disorders caused by protein aggregation. The first half of this paper will be focused on how mutations in HSPB1, HSPB3, and HSPB8 are linked to inherited peripheral neuropathies like Charcot-Marie-Tooth (CMT) disease and distal hereditary motor neuropathy (dHMN). The second part of the paper will discuss how small heat shock proteins are linked to neurodegenerative disorders like Alzheimer's, Parkinson's, and Huntington's disease.

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Section: Mutations In Shsps Causing Neurodegenerative Diseases Hspb1mentioning

confidence: 99%

Section: Mutations In Shsps Causing Neurodegenerative Diseases Hspb1mentioning

confidence: 99%

Section: Mutations In Shsps Causing Neurodegenerative Diseases Hspb1mentioning

confidence: 99%

See 1 more Smart Citation

Small heat shock proteins in neurodegenerative diseases

Vendredy

Adriaenssens

Timmerman

2020

Cell Stress and Chaperones

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“…These may be either due to toxic gain of function as a result of misfolding and aggregation or due to loss of function leading to decrease in the ability of cells to tolerate stress. Four mutant transgenic mouse models of dHMN were developed, and treatment with a selective HDAC6 inhibitor showed a reversal of the clinical phenotype of both S135F and P182L transgenic mice [48].…”

Section: Charcot-marie-tooth Diseasementioning

confidence: 99%

Therapeutic potential of Hsp27 in neurological diseases

Venugopal

Sundaramoorthy

Vellingiri

2019

Egypt J Med Hum Genet

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Background: Heat shock proteins (Hsps) are widely reported in normal cellular dynamics under stress and nonstress conditions, and parallelly, the studies regarding its role in disease condition are also progressing steadily. The function of Hsps in neurodegenerative disorders is puzzling and not fully understood. This review aims to focus on the role of Hsp27 in normal and diseased conditions and emphasize its therapeutic potential. Hsp27: Hsp27, in particular, has shown to be involved in cell viability and actin cytoskeleton remodeling and also shown to improve many disease conditions. Phosphorylated Hsp27 modulates the p53 pathway by downregulating cellular senescence and also lowers reactive oxygen species to protect TNFα-mediated apoptosis. Hsp27 is also known to interfere with mitochondria-dependent and mitochondria-independent cell apoptotic stimulation.Conclusion: This article will highlight the various functions of Hsp27 especially as an anti-apoptotic factor and stress response factor and its therapeutic potential in preventing neuronal apoptosis in neurological diseases. This review also includes a comparison of the therapeutic potential of Hsp27 with regard to other small Hsps.

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“…HSPB1 is a multifunctional protein with roles in protein aggregation (1–3), apoptosis (4–8), cytoskeletal maintenance (9–11), and gene transcription (12–14). Mutations in HSPB1 result in late-onset, distal hereditary motor neuropathy type II (dHMN) and axonal Charcot-Marie Tooth disease (CMT2F) (15–21). These neuropathies are characterized by length-dependent axonal degeneration of peripheral nerve axons, resulting in sensory loss, muscle wasting, and weakness (18, 22).…”

Section: Introductionmentioning

confidence: 99%

HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons

Heilman

Song

Miranda

et al. 2017

Experimental Neurology

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Heat shock protein beta-1 (HSPB1), is a ubiquitously expressed, multifunctional protein chaperone. Mutations in HSPB1 result in the development of a late-onset, distal hereditary motor neuropathy type II (dHMN) and axonal Charcot-Marie Tooth disease with sensory involvement (CMT2F). The functional consequences of HSPB1 mutations associated with hereditary neuropathy are unknown. HSPB1 also displays neuroprotective properties in many neuronal disease models, including the motor neuron disease amyotrophic lateral sclerosis (ALS). HSPB1 is upregulated in SOD1-ALS animal models during disease progression, predominately in glial cells. Glial cells are known to contribute to motor neuron loss in ALS through a non-cell autonomous mechanism. In this study, we examined the non-cell autonomous role of wild type and mutant HSPB1 in an astrocyte-motor neuron co-culture model system of ALS. Astrocyte-specific overexpression of wild type HSPB1 was sufficient to attenuate SOD1(G93A) astrocyte-mediated toxicity in motor neurons, whereas, overexpression of mutHSPB1 failed to ameliorate motor neuron toxicity. Expression of a phosphomimetic HSPB1 mutant in SOD1(G93A) astrocytes also reduced toxicity to motor neurons, suggesting that phosphorylation may contribute to HSPB1 mediated-neuroprotection. These data provide evidence that astrocytic HSPB1 expression may play a central role in motor neuron health and maintenance.

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Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene

Abstract: HighlightsMutations in HSPB1 result in a motor predominant neuropathy.The mean age of disease onset was in the 4th decade.HSPB1 neuropathy is characterised by early plantar flexion weakness.Muscle MRI demonstrates selective denervation of gastrocnemius and soleus.

Cited by 31 publications

References 16 publications

Small heat shock proteins in neurodegenerative diseases

Small heat shock proteins in neurodegenerative diseases

Therapeutic potential of Hsp27 in neurological diseases

HSPB1 mutations causing hereditary neuropathy in humans disrupt non-cell autonomous protection of motor neurons

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