Downregulation of proteins involved in the endoplasmic reticulum stress response and Nrf2-ARE signaling in lymphoblastoid cells of spinocerebellar ataxia type 17

Li Ching Lee, Yu Ting Weng, Yih Ru Wu, Bing Wen Soong, Yung-Che Tseng, Chiung Mei Chen, Guey-Jen Lee

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Spinocerebellar ataxia type 17 (SCA17) is caused by CAG repeat expansion in the TATA-box binding protein gene. Studies of several polyglutamine (polyQ) expansion diseases have suggested that the expanded polyQ proteins misfold and induce oxidative stress to contribute to cell death. Substantial deficits in peripheral tissues including lymphocytes have been shown and these peripheral abnormalities could also be found in neurons possessing polyQ disease proteins. In this study, we used a lymphoblastoid cell model to investigate the functional implication of SCA17 expanded alleles and assess the potential therapeutic strategies that may ameliorate the effects of expanded polyQ. Proteomics studies of patient/control pairs including two-dimensional (2-D) gel electrophoresis, mass spectrometry and immunoblotting were conducted. A total of 8 proteins with reduced expression changes greater than 1.3-fold were identified, including previously reported HSPA5 and HSPA8. Among 6 proteins further semi-quantified by immunoblotting and real-time PCR, the reduced expression of HYOU1, PDIA3, P4HB, NQO1 and HMOX1 was confirmed. Treatment with resveratrol and genipin up-regulated NQO1 and HMOX1 expression and reduced oxidative stress in patients' lymphoblastoid cells. The results illustrate downregulation of proteins involved in the endoplasmic reticulum stress response (HYOU1, HSPA5, PDIA3, and P4HB) and Nrf2-ARE signaling (NQO1 and HMOX1) in SCA17 lymphoblastoid cells. Compounds increasing anti-oxidative activity such as resveratrol and genipin may serve as a potential therapeutic strategy for SCA17.

Original languageEnglish
Pages (from-to)601-610
Number of pages10
JournalJournal of Neural Transmission
Volume121
Issue number6
DOIs
Publication statusPublished - 2014 Jan 1

Fingerprint

Endoplasmic Reticulum Stress
Down-Regulation
Proteins
Immunoblotting
Oxidative Stress
TATA-Box Binding Protein
Electrophoresis, Gel, Two-Dimensional
Proteomics
Real-Time Polymerase Chain Reaction
Mass Spectrometry
Cell Death
Therapeutics
Alleles
polyglutamine
Spinocerebellar Ataxia 17
Lymphocytes
Neurons
Genes

Keywords

  • Lymphoblastoid cells
  • Oxidative stress
  • Spinocerebellar ataxia type 17
  • TBP expansion
  • Therapeutics

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Downregulation of proteins involved in the endoplasmic reticulum stress response and Nrf2-ARE signaling in lymphoblastoid cells of spinocerebellar ataxia type 17. / Lee, Li Ching; Weng, Yu Ting; Wu, Yih Ru; Soong, Bing Wen; Tseng, Yung-Che; Chen, Chiung Mei; Lee, Guey-Jen.

In: Journal of Neural Transmission, Vol. 121, No. 6, 01.01.2014, p. 601-610.

Research output: Contribution to journalArticle

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abstract = "Spinocerebellar ataxia type 17 (SCA17) is caused by CAG repeat expansion in the TATA-box binding protein gene. Studies of several polyglutamine (polyQ) expansion diseases have suggested that the expanded polyQ proteins misfold and induce oxidative stress to contribute to cell death. Substantial deficits in peripheral tissues including lymphocytes have been shown and these peripheral abnormalities could also be found in neurons possessing polyQ disease proteins. In this study, we used a lymphoblastoid cell model to investigate the functional implication of SCA17 expanded alleles and assess the potential therapeutic strategies that may ameliorate the effects of expanded polyQ. Proteomics studies of patient/control pairs including two-dimensional (2-D) gel electrophoresis, mass spectrometry and immunoblotting were conducted. A total of 8 proteins with reduced expression changes greater than 1.3-fold were identified, including previously reported HSPA5 and HSPA8. Among 6 proteins further semi-quantified by immunoblotting and real-time PCR, the reduced expression of HYOU1, PDIA3, P4HB, NQO1 and HMOX1 was confirmed. Treatment with resveratrol and genipin up-regulated NQO1 and HMOX1 expression and reduced oxidative stress in patients' lymphoblastoid cells. The results illustrate downregulation of proteins involved in the endoplasmic reticulum stress response (HYOU1, HSPA5, PDIA3, and P4HB) and Nrf2-ARE signaling (NQO1 and HMOX1) in SCA17 lymphoblastoid cells. Compounds increasing anti-oxidative activity such as resveratrol and genipin may serve as a potential therapeutic strategy for SCA17.",
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