Small molecule modulator of protein disulfide isomerase attenuates mutant huntingtin toxicity and inhibits endoplasmic reticulum stress in a mouse model of Huntington's disease

Xiao Zhou, Gang Li, Anna Kaplan, Michael M. Gaschler, Xiaoyan Zhang, Zhipeng Hou, Mali Jiang, Roseann Zott, Serge Cremers, Brent R. Stockwell, Wenzhen Duan

Research output: Contribution to journalArticle

Abstract

Huntington's disease (HD) is caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin (HTT) gene encoding an elongated polyglutamine tract within the N-terminal of the huntingtin protein (Htt) and leads to Htt misfolding, aberrant protein aggregation, and progressive appearance of disease symptoms. Chronic activation of endoplasmic reticulum (ER) stress by mutant Htt (mHtt) results in cellular dysfunction and ultimately cell death. Protein disulfide isomerase (PDI) is a chaperone protein located in the ER. Our previous studies demonstrated that mHtt caused PDI to accumulate at mitochondria-associated ER membranes and triggered cell death, and that modulating PDI activity using small molecules protected cells again mHtt toxicity in cell and brain slice models of HD. In this study, we demonstrated that PDI is upregulated in the HD human brain, in cell and mouse models. Chronic administration of a reversible, brain penetrable small molecule PDI modulator, LOC14 (20 mg/kg/day), significantly improved motor function, attenuated brain atrophy and extended survival in the N171-82Q HD mice. Moreover, LOC14 preserved medium spiny neuronal marker dopamine- and cyclic-AMP-regulated phosphoprotein of molecular weight 32 000 (DARPP32) levels in the striatum of HD mice. Mechanistic study revealed that LOC14 suppressed mHtt-induced ER stress, indicated by repressing the abnormally upregulated ER stress proteins in HD models. These findings suggest that LOC14 is promising to be further optimized for clinical trials of HD, and modulation of signaling pathways coping with ER stress may constitute an attractive approach to reduce mHtt toxicity and identify new therapeutic targets for treatment of HD.

Original languageEnglish (US)
Pages (from-to)1545-1555
Number of pages11
JournalHuman Molecular Genetics
Volume27
Issue number9
DOIs
StatePublished - May 1 2018

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Protein Disulfide-Isomerases
Endoplasmic Reticulum Stress
Huntington Disease
Brain
Endoplasmic Reticulum
Cell Death
Trinucleotide Repeat Expansion
Phosphoproteins
Cytosine
Guanine
Adenine
Mutant Proteins
Heat-Shock Proteins
Cyclic AMP
Atrophy
Dopamine
Mitochondria
Proteins
Molecular Weight
Clinical Trials

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Small molecule modulator of protein disulfide isomerase attenuates mutant huntingtin toxicity and inhibits endoplasmic reticulum stress in a mouse model of Huntington's disease. / Zhou, Xiao; Li, Gang; Kaplan, Anna; Gaschler, Michael M.; Zhang, Xiaoyan; Hou, Zhipeng; Jiang, Mali; Zott, Roseann; Cremers, Serge; Stockwell, Brent R.; Duan, Wenzhen.

In: Human Molecular Genetics, Vol. 27, No. 9, 01.05.2018, p. 1545-1555.

Research output: Contribution to journalArticle

Zhou, Xiao ; Li, Gang ; Kaplan, Anna ; Gaschler, Michael M. ; Zhang, Xiaoyan ; Hou, Zhipeng ; Jiang, Mali ; Zott, Roseann ; Cremers, Serge ; Stockwell, Brent R. ; Duan, Wenzhen. / Small molecule modulator of protein disulfide isomerase attenuates mutant huntingtin toxicity and inhibits endoplasmic reticulum stress in a mouse model of Huntington's disease. In: Human Molecular Genetics. 2018 ; Vol. 27, No. 9. pp. 1545-1555.
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AU - Zhang, Xiaoyan

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AU - Jiang, Mali

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AB - Huntington's disease (HD) is caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin (HTT) gene encoding an elongated polyglutamine tract within the N-terminal of the huntingtin protein (Htt) and leads to Htt misfolding, aberrant protein aggregation, and progressive appearance of disease symptoms. Chronic activation of endoplasmic reticulum (ER) stress by mutant Htt (mHtt) results in cellular dysfunction and ultimately cell death. Protein disulfide isomerase (PDI) is a chaperone protein located in the ER. Our previous studies demonstrated that mHtt caused PDI to accumulate at mitochondria-associated ER membranes and triggered cell death, and that modulating PDI activity using small molecules protected cells again mHtt toxicity in cell and brain slice models of HD. In this study, we demonstrated that PDI is upregulated in the HD human brain, in cell and mouse models. Chronic administration of a reversible, brain penetrable small molecule PDI modulator, LOC14 (20 mg/kg/day), significantly improved motor function, attenuated brain atrophy and extended survival in the N171-82Q HD mice. Moreover, LOC14 preserved medium spiny neuronal marker dopamine- and cyclic-AMP-regulated phosphoprotein of molecular weight 32 000 (DARPP32) levels in the striatum of HD mice. Mechanistic study revealed that LOC14 suppressed mHtt-induced ER stress, indicated by repressing the abnormally upregulated ER stress proteins in HD models. These findings suggest that LOC14 is promising to be further optimized for clinical trials of HD, and modulation of signaling pathways coping with ER stress may constitute an attractive approach to reduce mHtt toxicity and identify new therapeutic targets for treatment of HD.

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