Mutant small heat shock protein B3 causes motor neuropathy

Kolb, Stephen J.; Snyder, Pamela J.; Poi, E. J.; Renard, Emilie; Bartlett, Anna; Gu, Shaohua; Sutton, Scott; Arnold, W. David; Freimer, Miriam; Lawson, Victoria H.; Kissel, John T.; Prior, Thomas W.

doi:10.1212/wnl.0b013e3181cef84a

Cited by 92 publications

(60 citation statements)

References 33 publications

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“…Heat shock protein 3 seems to participate in the mechanisms of cell survival (Sugiyama et al, 2000). It was shown that HSPB3 (R7S) mutation was associated with an axonal motor neuropathy (Kolb et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…It was demonstrated that the expression of HSPB3 and MKBP/HSPB2 was induced during muscle differentiation, suggesting that the sHSP oligomer comprising HSPB3 and MKBP/HSPB2 represents an additional system closely related to muscle function (Sugiyama et al, 2000). Also it was supposed that HSPB3 plays an important role in motor neuron viability (Kolb et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Map3k1, Il6st, Gzmk, and Hspb3 gene coexpression network in the mechanism of freezing reaction in mice

Кондаурова

Науменко

Sinyakova

et al. 2010

J of Neuroscience Research

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Freezing reaction (catalepsy) is a natural passive defensive strategy in animals. An exaggerated form of catalepsy is a symptom of grave brain dysfunction. Catalepsy in mice was shown to be linked to the Map3k1, Il6st, Gzmk, and Hspb3 genes as potential candidates for a high predisposition to catalepsy. The study sought to test the hypothesis of an association between catalepsy and expression of these genes in the brain. Thegenes' mRNA levels were measured in the hypothalamus, hippocampus, frontal cortex, striatum, and midbrain of catalepsy-resistant AKR/J strain and catalepsy-prone strains CBA/Lac, ASC (antidepressant-sensitive cataleptic) and the congenic line AKR.CBA-D13M76C. No association between expression of any investigated genes and predisposition to catalepsy was found. At the same time, multivariate analysis revealed interactions among the expressions of Map3k1, Il6st, Gzmk, and Hspb3 genes in the brain structures. A factor analysis of all variables produced two independent factors explaining 76.2% of the total variance. The catalepsy-resistant AKR strain was distinguished from the catalepsy-prone strains CBA, ASC, and AKR.CBA-D13M76C by factor 1. It was suggested that a high predisposition to catalepsy in mice can be defined by the Map3k1, Il6st, Gzmk, and Hspb3 genes' coexpression network.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Map3k1, Il6st, Gzmk, and Hspb3 gene coexpression network in the mechanism of freezing reaction in mice

Кондаурова

Науменко

Sinyakova

et al. 2010

J of Neuroscience Research

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“…This is further supported by the fact that mutations of several HSPB proteins (HSPB1, HSPB3, HSPB4, HSPB5, HSPB8) are associated with muscular and neurological disorders, including hereditary sensory and/or motor neuropathy (e.g. HSPB1, HSPB3, HSPB8), myofi brillar myopathy (HSPB5) and congenital cataract (HSPB4) Irobi et al 2004 ;Evgrafov et al 2004 ;Kolb et al 2010 ;Litt et al 1998 ;Vicart et al 1998 ). In this chapter we will focus on the potentially protective function exerted by HSPB8 in neurodegenerative and neuromuscular diseases and we will highlight how HSPB8 may act at the crossroad of both protein synthesis and protein degradation, thereby participating in the maintenance of proteostasis.…”

Section: Hspbs: Implication In Neurodegenerative and Neuromuscular DImentioning

confidence: 92%

Role of HSPB8 in the Proteostasis Network: From Protein Synthesis to Protein Degradation and Beyond

Poletti

Carra

2015

Heat Shock Proteins

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Proper protein folding is crucial for protein stability and function; when folding fails, due to stress or genetic mutations, proteins may become toxic. Cells have evolved a complex protein quality control (PQC) system to protect against the toxicity exerted by aberrantly folded proteins, that may aggregate accumulating in various cellular compartments perturbing essential cellular activities, ultimately leading to cell and neuron death. The PQC comprises molecular chaperones, degradative systems (proteasome and autophagy) and components of the unfolded protein response. Prevention of protein aggregation, clearance of misfolded substrates and attenuation of translation, which decreases the amount of misfolding clients to levels manageable by the molecular chaperones, are all key steps for the maintenance of proteostasis and cell survival. In parallel, alterations of proteostasis may also (indirectly) infl uence RNA homeostasis; in fact, RNA-containing aggregates, known as stress granules, accumulate in cells with impaired PQC and autophagy colocalizing with proteinaceous aggregates in several neurodegenerative diseases. Among the different molecular chaperones, here we will focus on the small heat shock protein HSPB8, which is expressed in neurons in basal conditions and upregulated in response to misfolded protein accumulation. HSPB8 exerts protective functions in several models of protein conformation neurodegenerative diseases. The putative sites of action of HSPB8 that confer HSPB8 pro-survival and anti-aggregation functions are discussed, as well as its potential role at the crossroad between proteostasis and ribostasis.

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“…For example, bicaudal D homolog 2 (BICD2) [187][188][189], dynactin 1 (DCTN1) [190], vesicle-trafficking protein (VAPB) [191], and cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) [192,193] are identified as causative genes of some HMNs. Some are involved in cargo packaging and retrograde axonal transport [194], while mutations in some of heat shock protein family which may cause the dysregulation of protein metabolism also induce HMNs [195][196][197]. Hence, it would be interesting to investigate their roles with SMN, and whether these genes are differentially regulated, thereby leading to selective motor neurone vulnerability.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Spinal muscular atrophy: Factors that modulate motor neurone vulnerability

Simpson

Highley

et al. 2017

Neurobiology of Disease

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Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the selective loss of particular groups of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. To date, no effective treatment is available, however, there are ongoing clinical trials are in place which promise much for the future. However, there remains an ongoing problem in trying to link a single gene loss to motor neurone degeneration. Fortunately, given successful disease models that have been established and intensive studies on SMN functions in the past ten years, we are fast approaching the stage of identifying the underlying mechanisms of SMA pathogenesis Here we discuss potential disease modifying factors on motor neurone vulnerability, in the belief that these factors give insight into the pathological mechanisms of SMA and therefore possible therapeutic targets. Keywords:Selective vulnerability, SMA, SMN, disease modifier, motor neurone disease ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T Highlights: Factors that influence vulnerability of motor neurons in SMA. SMA disease modification. Impact of surrounding cells on neuronal death. Precise molecular defects in SMA; mRNA splicing and miRNA interactions. Cytoskeletal stability and axonal transport effects.

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Mutant small heat shock protein B3 causes motor neuropathy

Abstract: The discovery of an HSPB3 mutation associated with an axonal motor neuropathy using a candidate gene approach supports the notion that the small heat shock protein gene family coordinately plays an important role in motor neuron viability.

Cited by 92 publications

References 33 publications

Map3k1, Il6st, Gzmk, and Hspb3 gene coexpression network in the mechanism of freezing reaction in mice

Map3k1, Il6st, Gzmk, and Hspb3 gene coexpression network in the mechanism of freezing reaction in mice

Role of HSPB8 in the Proteostasis Network: From Protein Synthesis to Protein Degradation and Beyond

Spinal muscular atrophy: Factors that modulate motor neurone vulnerability

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