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Hum Mol Genet. 2018 May 1;27(9):1545-1555. doi: 10.1093/hmg/ddy061.

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

Author information

1
Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
2
Department of Pharmacology, Pharmacy School, Inner Mongolian Medical University, Hohhot, Inner Mongolian, 010110, China.
3
Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
4
Department of Chemistry, Columbia University, New York, NY 10027, USA.
5
Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
6
Irving Institute for Clinical and Translational Research, Columbia University Medical Center, New York, NY 10027, USA.
7
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10027, USA.
8
Department of Medicine, Columbia University Medical Center, New York, NY 10027, USA.
9
Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
10
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

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.

PMID:
29462355
PMCID:
PMC5905666
DOI:
10.1093/hmg/ddy061
[Indexed for MEDLINE]
Free PMC Article

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