Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 671-682 |
| Number of pages | 12 |
| Journal | Journal of Neuroscience Research |
| Volume | 94 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 2016 |
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Keywords
- ALS
- Alzheimer's disease
- Heat shock factor 1
- Heat shock proteins
- Lou Gehrig's disease
- Protein aggregation
- RRID:AB_10979281
- RRID:AB_10987450
- RRID:AB_1659604
- RRID:AB_2039260
- RRID:AB_2532125
- RRID:AB_2532126
- RRID:AB_528498
- RRID:AB_637828
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
Cite this
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, Pei Yi; Folorunso, Oluwarotimi; Taglialatela, Giulio; Pierce, Anson.
In: Journal of Neuroscience Research, Vol. 94, No. 7, 01.07.2016, p. 671-682.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Overexpression of heat shock factor 1 maintains TAR DNA binding protein 43 solubility via induction of inducible heat shock protein 70 in cultured cells
AU - Lin, Pei Yi
AU - Folorunso, Oluwarotimi
AU - Taglialatela, Giulio
AU - Pierce, Anson
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
KW - ALS
KW - Alzheimer's disease
KW - Heat shock factor 1
KW - Heat shock proteins
KW - Lou Gehrig's disease
KW - Protein aggregation
KW - RRID:AB_10979281
KW - RRID:AB_10987450
KW - RRID:AB_1659604
KW - RRID:AB_2039260
KW - RRID:AB_2532125
KW - RRID:AB_2532126
KW - RRID:AB_528498
KW - RRID:AB_637828
UR - http://www.scopus.com/inward/record.url?scp=84961848572&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961848572&partnerID=8YFLogxK
U2 - 10.1002/jnr.23725
DO - 10.1002/jnr.23725
M3 - Article
C2 - 26994698
AN - SCOPUS:84961848572
VL - 94
SP - 671
EP - 682
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 7
ER -