Heat shock factor 1 over-expression protects against exposure of hydrophobic residues on mutant SOD1 and early mortality in a mouse model of amyotrophic lateral sclerosis

Lin, Pei; Simon, Sharotka M.; Koh, Won Kyun; Folorunso, Oluwarotimi; Umbaugh, Charles S.; Pierce, Anson

doi:10.1186/1750-1326-8-43

Cited by 37 publications

(41 citation statements)

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“…We have previously shown that overexpression of heat shock factor 1 (HSF1), the master transcription factor for HSPs, has protective effects in ALS and AD mouse models (Lin et al, ; Pierce et al, ). HSF1 increased the solubility of mutant SOD1 concomitantly with delayed disease onset (Lin et al, ) and ameliorated AD‐like cognitive impairment (Pierce et al, ). Other studies have shown that multiple HSPs are responsible for TDP‐43 homeostasis and metabolism.…”

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confidence: 99%

Overexpression of heat shock factor 1 maintains TAR DNA binding protein 43 solubility via induction of inducible heat shock protein 70 in cultured cells

Lin

Folorunso

Taglialatela

et al. 2016

J of Neuroscience Research

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TAR DNA binding protein 43 (TDP-43) is a nuclear protein that has been shown to have altered homeostasis in the form of neuronal nuclear and cytoplasmic aggregates in some familial and almost all cases of sporadic amyotrophic lateral sclerosis as well as 51% of frontotemporal lobar degeneration and 57% of Alzheimer's disease cases. Heat shock proteins (HSPs), such as HSP70, recognize misfolded or aggregated proteins and refold, disaggregate, or turn them over and are upregulated by the master transcription factor heat shock factor 1 (HSF1). Here, we explore the effect of HSF1 overexpression on proteotoxic stress-related alterations in TDP-43 solubility, proteolytic processing, and cytotoxicity. HSF1 overexpression reduced TDP-43-positive puncta concomitantly with upregulating HSP70 and HSP90 protein levels. HSF1 overexpression or pharmacological activation sustained TDP-43 solubility and significantly reduced truncation of TDP-43 in response to inhibition of the proteasome with Z-Leu-Leu-Leu-al, and this was reversed by HSF1 inhibition. HSF1 activation conferred protection against toxicity associated with TDP-43 C-terminal fragments without globally increasing the activity of the ubiquitin proteasome system (UPS) while concomitantly reducing the induction of autophagy, suggesting that HSF1 protection is an early event. In support of this, inhibition of HSP70 ATPase activity further reduced TDP-43 solubility. HSF1 knockout significantly increased TDP-43 insolubility and accelerated TDP-43 fragmentation in response to proteotoxic stress. Overall, this study shows that HSF1 overexpression protects against TDP-43 pathology by upregulation of chaperones, especially HSP70, rather than enhancing autophagy or the UPS during times of proteotoxic stress. © 2016 Wiley Periodicals, Inc.

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confidence: 99%

Overexpression of heat shock factor 1 maintains TAR DNA binding protein 43 solubility via induction of inducible heat shock protein 70 in cultured cells

Lin

Folorunso

Taglialatela

et al. 2016

J of Neuroscience Research

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“…small HSP HSP27 (HSPB1) AD/ Aβ Reduced Aβ aggregation in vitro and toxicity on cells [98] and in mice [99]; alters tau dynamics in mice [100]; reduced polyQ aggregation and toxicity in cells [101] and by viral delivery in rats [102] but not transgenic mice [103]; reduced α-synuclein fibril AD/Tau HD/Htt AD deficits in mice [120]; polyQ in mice [121]; mutant SOD1 in mice [122].…”

Section: Chaperone Family Chaperone Disease/protein(s) Commentsmentioning

confidence: 99%

Molecular chaperones and neuronal proteostasis

Smith¹,

Li²,

Cheetham³

2015

Seminars in Cell & Developmental Biology

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Protein homeostasis (proteostasis) is essential for maintaining the functionality of the proteome. The disruption of proteostasis, due to genetic mutations or an age-related decline, leads to aberrantly folded proteins that typically lose their function. The accumulation of misfolded and aggregated protein is also cytotoxic and has been implicated in the pathogenesis of neurodegenerative diseases. Neurons have developed an intrinsic protein quality control network, of which molecular chaperones are an essential component. Molecular chaperones function to promote efficient folding and target misfolded proteins for refolding or degradation. Increasing molecular chaperone expression can suppress protein aggregation and toxicity in numerous models of neurodegenerative disease; therefore, molecular chaperones are considered exciting therapeutic targets. Furthermore, mutations in several chaperones cause inherited neurodegenerative diseases. In this review, we focus on the importance of molecular chaperones in neurodegenerative diseases, and discuss the advances in understanding their protective mechanisms.

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“…Induction of HSP40/70 in spinal cords of G93A SOD1 mice, by 2–3 fold, has been demonstrated by transgenic over‐expression of HSF1, using a transgene vector that expresses in both neurons and astrocytes (Lin et al . ). This report did not provide histologic evaluation of which cells responded to the added HSF1 expression.…”

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confidence: 97%

“…Although this study reported that the age at which mice that were bigenic for the G93A mutant SOD1 and HSF1 first developed symptoms was later than that of mice that express the G93A mutant alone, on the whole, the average age to paralysis for bigenic mice was not statistically different from that of mice expressing SOD1‐G93A alone (Lin et al . ). Collectively, these studies provide a mixed view of the potential efficacy of inducible HSPs in ameliorating the phenotypes caused by expression of mutant SOD1.…”

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Substantially elevating the levels of αB‐crystallin in spinal motor neurons of mutant SOD1 mice does not significantly delay paralysis or attenuate mutant protein aggregation

Fromholt

Ayers

et al. 2015

Journal of Neurochemistry

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There has been great interest in enhancing endogenous protein maintenance pathways such as the heat-shock chaperone response, as it is postulated that enhancing clearance of misfolded proteins could have beneficial disease modifying effects in ALS and other neurodegenerative disorders. In cultured cell models of mutant SOD1 aggregation, co-expression of αB-crystallin (αB-crys) has been shown to inhibit the formation of detergent-insoluble forms of mutant protein. Here, we describe the generation of a new line of transgenic mice that express αB-crys at >6-fold the normal level in spinal cord, with robust increases in immunoreactivity throughout the spinal cord grey matter and, specifically, in spinal motor neurons. Surprisingly, spinal cords of mice expressing αB-crys alone contained 20% more motor neurons per section than littermate controls. Raising αB-crys by these levels in mice transgenic for either G93A or L126Z mutant SOD1 had no effect on the age at which paralysis developed. In the G93A mice, which showed the most robust degree of motor neuron loss, the number of these cells declined by the same proportion as in mice expressing the mutant SOD1 alone. In paralyzed bigenic mice, the levels of detergent-insoluble, misfolded, mutant SOD1 were similar to those of mice expressing mutant SOD1 alone. These findings indicate that raising the levels of αB-crys in spinal motor neurons by 6-fold does not produce the therapeutic effects predicted by cell culture models of mutant SOD1 aggregation.

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Heat shock factor 1 over-expression protects against exposure of hydrophobic residues on mutant SOD1 and early mortality in a mouse model of amyotrophic lateral sclerosis

Cited by 37 publications

References 78 publications

Overexpression of heat shock factor 1 maintains TAR DNA binding protein 43 solubility via induction of inducible heat shock protein 70 in cultured cells

Overexpression of heat shock factor 1 maintains TAR DNA binding protein 43 solubility via induction of inducible heat shock protein 70 in cultured cells

Molecular chaperones and neuronal proteostasis

Substantially elevating the levels of αB‐crystallin in spinal motor neurons of mutant SOD1 mice does not significantly delay paralysis or attenuate mutant protein aggregation

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