Knockdown of Heat Shock Proteins HSPA6 (Hsp70B’) and HSPA1A (Hsp70-1) Sensitizes Differentiated Human Neuronal Cells to Cellular Stress

Deane, Catherine A. S.; Brown, Ian R.

doi:10.1007/s11064-017-2429-z

Cited by 24 publications

(23 citation statements)

References 34 publications

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“…Celastrol is a pentacyclic triterpenoid isolated from the root extracts of Tripterygium wilfordii (Thunder god vine) and Celastrus regelii . It was demonstrated that celastrol activates HSF1, the master regulator of Hsp gene transcription [ 300 ], and induces Hsp70 within dopaminergic neurons [ 301 ]. Low dose co-application of celastrol and arimoclomol induces HspA1A (Hsp70-1) and HspA6 (Hsp70B’) as such enhancing the ability of differentiated SH-SY5Y neuronal cells to survive heat shock.…”

Section: Prevention and Treatment Of Nddsmentioning

confidence: 99%

“…Low dose co-application of celastrol and arimoclomol induces HspA1A (Hsp70-1) and HspA6 (Hsp70B’) as such enhancing the ability of differentiated SH-SY5Y neuronal cells to survive heat shock. Small interfering RNA (siRNA) knockdown of HspA6 and HspA1A results in loss of the protective effect of co-application of celastrol and arimoclomol [ 300 ]. Celastrol is a potent inhibitor of lipid peroxidation [ 302 , 303 ] and inhibits induced NO production in mouse brain endothelial cells in a dose-dependent manner [ 304 ].…”

Section: Prevention and Treatment Of Nddsmentioning

confidence: 99%

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Heat Shock Proteins and Autophagy Pathways in Neuroprotection: From Molecular Bases to Pharmacological Interventions

Penke

Bogár

Crul

et al. 2018

IJMS

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Neurodegenerative diseases (NDDs) such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease (HD), amyotrophic lateral sclerosis, and prion diseases are all characterized by the accumulation of protein aggregates (amyloids) into inclusions and/or plaques. The ubiquitous presence of amyloids in NDDs suggests the involvement of disturbed protein homeostasis (proteostasis) in the underlying pathomechanisms. This review summarizes specific mechanisms that maintain proteostasis, including molecular chaperons, the ubiquitin-proteasome system (UPS), endoplasmic reticulum associated degradation (ERAD), and different autophagic pathways (chaperon mediated-, micro-, and macro-autophagy). The role of heat shock proteins (Hsps) in cellular quality control and degradation of pathogenic proteins is reviewed. Finally, putative therapeutic strategies for efficient removal of cytotoxic proteins from neurons and design of new therapeutic targets against the progression of NDDs are discussed.

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Section: Prevention and Treatment Of Nddsmentioning

confidence: 99%

Section: Prevention and Treatment Of Nddsmentioning

confidence: 99%

Heat Shock Proteins and Autophagy Pathways in Neuroprotection: From Molecular Bases to Pharmacological Interventions

Penke

Bogár

Crul

et al. 2018

IJMS

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“…The highly conserved HSPA6 gene (Daugaard, Rohde, & Jäättelä, ; Gupta & Golding, ) belongs to the multigene HSP family A (HSP70). Little is known about the function of HSPA6 , a gene present in the human genome but absent from mouse and rat (Deane & Brown, ). To our knowledge, there are no animal models for functional screening of the orthologous gene although it is present in other vertebrates and species such as frog, fruit fly, or yeast (Table ).…”

Section: Discussionmentioning

confidence: 99%

“…To our knowledge, there are no animal models for functional screening of the orthologous gene although it is present in other vertebrates and species such as frog, fruit fly, or yeast (Table ). Emerging research suggests the HSPA6 protein to be involved in apoptotic response and cellular differentiation and to contribute to protection of differentiated human neuronal cells from cellular stress (Deane & Brown, ). Only when induced after severe stress events (Parsian et al, ), it functions as a secondary responder to proteotoxic stress and maintains cellular survival by directly binding to Apaf‐1 and inhibiting the assembly of a functional apoptosome (Beere et al, ; Noonan, Place, Giardina, & Hightower, ).…”

Section: Discussionmentioning

confidence: 99%

HSPA6: A new autosomal recessive candidate gene for the VATER/VACTERL malformation spectrum

Kause

Zhang

Ludwig

et al. 2019

Birth Defects Research

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Background The VATER/VACTERL association refers to the nonrandom co‐occurrence of at least three of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Patients presenting with two CFs have been termed VATER/VACTERL‐like phenotypes. Methods We surveyed the exome for recessive disease variants in three affected sib‐pairs. Sib‐pair 971 consisted of two brothers with ARM and additional hydronephrosis in one brother. Sib‐pair 1098 consisted of two sisters with ARM. In family 1346, the daughter presented with ARM and additional hypoplasia of both small fingers and ankyloses. Her brother presented with unilateral isolated radial hypoplasia. Sib‐pairs 971 and 1346 resembled a VATER/VACTERL‐like phenotype. Results We detected a novel maternally inherited missense variant (c.1340G > T) and a rare paternally inherited deletion of the trans‐allele in HSPA6 in both siblings of family 1346. HSPA6 belongs to the heat shock protein (HSP) 70 family. Re‐sequencing of HSPA6 in 167 patients with VATER/VACTERL and VATER/VACTERL‐like phenotypes did not reveal any additional bi‐allelic variants. Conclusions Until now, only TNF‐receptor associated protein 1 (TRAP1) had been reported as an autosomal recessive disease‐gene for the VATER/VACTERL association. TRAP1 belongs to the heat shock protein 90 family (HSP90). Both Hsp70 and Hsp90 genes have been shown to be important embryonic drivers in the formation of mouse embryonic forelimb tissue. Our results suggest HSPA6 as a new candidate gene in VATER/VACTERL‐like phenotypes.

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“…Celastrol has been tested as a neuroprotectant in various models of neurodegeneration with a beneficial outcome (Deane & Brown, ; Faust et al., ; Gu et al., ; Jantas et al., ; Kyung et al., ; Sun et al., ; Xu et al., ; Zhang et al., ) by inducing rapid HSP70 expression (Allison et al., ; Cascão, Fonseca, & Moita, ; Chow & Brown, ; DeMeester, Buchman, & Cobb, ; Kannaiyan, Shanmugam, & Sethi, ; Salminen et al., ; Traynor et al., ; Trott et al., ; Welsh, Moyer, & Harris, ; Westerheide et al., ). Its action on spinal excitotoxicity remains, however, to be studied.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological induction of Heat Shock Protein 70 by celastrol protects motoneurons from excitotoxicity in rat spinal cord in vitro

Petrović

Kaur

Tomljanović

et al. 2018

Eur J of Neuroscience

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The secondary phase of spinal cord injury arising after the primary lesion largely extends the damage severity with delayed negative consequences for sensory‐motor pathways. It is, therefore, important to find out if enhancing intrinsic mechanisms of neuroprotection can spare motoneurons that are very vulnerable cells. This issue was investigated with an in vitro model of rat spinal cord excitotoxicity monitored for up to 24 hr after the primary injury evoked by kainate. This study sought to pharmacologically boost the expression of heat shock proteins (HSP) to protect spinal motoneurons using celastrol to investigate if the rat spinal cord can upregulate HSP as neuroprotective mechanism. Despite its narrow range of drug safety in vitro, celastrol was not toxic to the rat spinal cord at 0.75 μM concentration and enhanced the expression of HSP70 by motoneurons. When celastrol was applied either before or after kainate, the number of dead motoneurons was significantly decreased and the nuclear localization of the cell death biomarker AIF strongly inhibited. Nevertheless, electrophysiological recording showed that protection of lumbar motor networks by celastrol was rather limited as reflex activity was impaired and fictive locomotion largely depressed, suggesting that functional deficit persisted, though the networks could express slow rhythmic oscillations. While our data do not exclude further recovery at later times beyond the experimental observations, the present results indicate that the upregulated expression of HSP in the aftermath of acute injury may be an interesting avenue for early protection of spinal motoneurons.

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Knockdown of Heat Shock Proteins HSPA6 (Hsp70B’) and HSPA1A (Hsp70-1) Sensitizes Differentiated Human Neuronal Cells to Cellular Stress

Cited by 24 publications

References 34 publications

Heat Shock Proteins and Autophagy Pathways in Neuroprotection: From Molecular Bases to Pharmacological Interventions

Heat Shock Proteins and Autophagy Pathways in Neuroprotection: From Molecular Bases to Pharmacological Interventions

HSPA6: A new autosomal recessive candidate gene for the VATER/VACTERL malformation spectrum

Pharmacological induction of Heat Shock Protein 70 by celastrol protects motoneurons from excitotoxicity in rat spinal cord in vitro

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