Up-regulation of inducible heat shock protein-70 expression in multiple sclerosis patients

Mansilla, María José; Comabella, Manuel; Río, Jordi; Castilló, Joaquín; Castillo, Mireia; Martin, Roland; Montalbán, Xavier; Espejo, Carmen

doi:10.3109/08916934.2013.866104

Cited by 18 publications

(8 citation statements)

References 43 publications

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“…Both C9orf72 and SOD1 ALS zebrafish models express a hsp70 promotor which drives DsRed protein production. Cell stress from a variety of insults increases the drive on the hsp70 promotor, and upregulation of the HSP70 protein has been reported in neurodegenerative disorders such as multiple sclerosis and, in the present study, ALS [ 19 , 23 , 27 ]. Therefore, in our ALS zebrafish models, the abundance of DsRed produced via hsp70 promotor activation is used as a readout of cellular stress.…”

Section: Resultsmentioning

confidence: 66%

Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features

Shaw

Higginbottom

McGown

et al. 2018

acta neuropathol commun

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A hexanucleotide repeat expansion (HRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is the most prevalent cause of amyotrophic lateral sclerosis/fronto-temporal dementia (ALS/FTD). Current evidence suggests HREs induce neurodegeneration through accumulation of RNA foci and/or dipeptide repeat proteins (DPR). C9orf72 patients are known to have transactive response DNA binding protein 43 kDa (TDP-43) proteinopathy, but whether there is further cross over between C9orf72 pathology and the pathology of other ALS sub-types has yet to be revealed.To address this, we generated and characterised two zebrafish lines expressing C9orf72 HREs. We also characterised pathology in human C9orf72-ALS cases. In addition, we utilised a reporter construct that expresses DsRed under the control of a heat shock promoter, to screen for potential therapeutic compounds.Both zebrafish lines showed accumulation of RNA foci and DPR. Our C9-ALS/FTD zebrafish model is the first to recapitulate the motor deficits, cognitive impairment, muscle atrophy, motor neuron loss and mortality in early adulthood observed in human C9orf72-ALS/FTD. Furthermore, we identified that in zebrafish, human cell lines and human post-mortem tissue, C9orf72 expansions activate the heat shock response (HSR). Additionally, HSR activation correlated with disease progression in our C9-ALS/FTD zebrafish model. Lastly, we identified that the compound ivermectin, as well as riluzole, reduced HSR activation in both C9-ALS/FTD and SOD1 zebrafish models.Thus, our C9-ALS/FTD zebrafish model is a stable transgenic model which recapitulates key features of human C9orf72-ALS/FTD, and represents a powerful drug-discovery tool.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0629-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 66%

Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features

Shaw

Higginbottom

McGown

et al. 2018

acta neuropathol commun

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“…Involvement of HSPs in the pathogenesis of several autoimmune diseases, such as Systemic Lupus Erythematosus 52 , diabetes 53 and multiple sclerosis 54 were reported. Elevated levels of serum HSP70-antibodies could be found in patients with generalized and ocular MG 55 .…”

Section: Discussionmentioning

confidence: 99%

HSP27 and 70 expression in thymic epithelial tumors and benign thymic alterations: diagnostic, prognostic and physiologic implications

Janik

Schiefer

Bekos

et al. 2016

Sci Rep

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Thymic Epithelial Tumors (TETs), the most common tumors in the anterior mediastinum in adults, show a unique association with autoimmune Myasthenia Gravis (MG) and represent a multidisciplinary diagnostic and therapeutic challenge. Neither risk factors nor established biomarkers for TETs exist. Predictive and diagnostic markers are urgently needed. Heat shock proteins (HSPs) are upregulated in several malignancies promoting tumor cell survival and metastases. We performed immunohistochemical staining of HSP27 and 70 in patients with TETs (n = 101) and patients with benign thymic alterations (n = 24). Further, serum HSP27 and 70 concentrations were determined in patients with TETs (n = 46), patients with benign thymic alterations (n = 33) and volunteers (n = 49) by using ELISA. HSPs were differentially expressed in histologic types and pathological tumor stages of TETs. Weak HSP tumor expression correlated with worse freedom from recurrence. Serum HSP concentrations were elevated in TETs and MG, correlated with clinical tumor stage and histologic subtype and decreased significantly after complete tumor resection. To conclude, we found HSP expression in the vast majority of TETs, in physiologic thymus and staining intensities in patients with TETs have been associated with prognosis. However, although interesting and promising the role of HSPs in TETs as diagnostic and prognostic or even therapeutic markers need to be further evaluated.

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“… 23 Different publications show a great diversity of intracellular Hsp70 levels in PBMCs of MS patients ranging from low 24 to normal 25 to elevated levels. 26 In the extracellular milieu, only Hsp70-specific antibodies 20 but not Hsp70 proteins have been determined in the serum of MS patients.…”

Section: Introductionmentioning

confidence: 99%

Serum heat shock protein 70 levels as a biomarker for inflammatory processes in multiple sclerosis

Lechner

Sick

Hemmer

et al. 2018

Multiple Sclerosis Journal - Experimental, Translational and Cl

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BackgroundInflammatory and neurodegenerative processes are hallmarks of multiple sclerosis (MS). The synthesis of the major stress-inducible heat shock protein 70 (Hsp70) is induced by inflammation.ObjectiveThe purpose of this study is to determine whether Hsp70 in serum can serve as a potential biomarker to distinguish inflammatory and neurodegenerative processes in MS.MethodsSerum was obtained from 94 patients: 26 clinically isolated syndrome (CIS), 40 relapsing–remitting MS (RRMS), 19 secondary progressive MS (SPMS), and nine primary progressive MS (PPMS). As controls, serum samples were collected from patients with non-inflammatory neurological diseases (NINDs, n = 41), other inflammatory neurological diseases (OINDs, n = 28) and healthy donors (HDs, n = 114). Serum levels of Hsp70 were quantified using the enzyme-linked immunosorbent assay detecting free and liposomal Hsp70 (lipHsp70 ELISA).ResultsPatients with MS displayed significantly higher Hsp70 serum levels than HDs (p < 0.001) and significantly lower levels than OINDs (p = 0.001). A subgroup analysis revealed that Hsp70 serum levels of CIS/RRMS patients are significantly higher than those of patients with progressive MS (SPMS/PPMS) (p < 0.05).ConclusionInflammation causes the release of Hsp70 into the blood. As CIS/RRMS are associated with higher Hsp70 serum levels than progressive MS, serum Hsp70 levels might provide a marker for inflammatory processes.

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Up-regulation of inducible heat shock protein-70 expression in multiple sclerosis patients

Cited by 18 publications

References 43 publications

Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features

Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features

HSP27 and 70 expression in thymic epithelial tumors and benign thymic alterations: diagnostic, prognostic and physiologic implications

Serum heat shock protein 70 levels as a biomarker for inflammatory processes in multiple sclerosis

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