Proteomic Analysis of Huntingtin-Associated Proteins Provides Clues to Altered Cell Homeostasis in Huntington’s Disease

HD (Huntington's disease) is a devastating neurodegenerative genetic disorder caused by abnormal expansion of CAG repeats in the HTT (huntingtin) gene. We have recently established two iPSC (induced pluripotent stem cell) lines derived from a HD patient carrying 72 CAG repeats (HD-iPSC). In order to understand the proteomic profiles of HD-iPSCs, we have performed comparative proteomic analysis among normal hESCs (human embryonic stem cells; H9), iPSCs (551-8) and HD-iPSCs at undifferentiated stages, and identified 26 up- and down-regulated proteins. Interestingly, these differentially expressed proteins are known to be involved in different biological processes, such as oxidative stress, programmed cell death and cellular oxygen-associated proteins. Among them, we found that oxidative stress-related proteins, such as SOD1 (superoxide dismutase 1) and Prx (peroxiredoxin) families are particularly affected in HD-iPSCs, implying that HD-iPSCs are highly susceptible to oxidative stress. We also found that BTF3 (basic transcription factor 3) is up-regulated in HD-iPSCs, which leads to the induction of ATM (ataxia telangiectasia mutated), followed by activation of the p53-mediated apoptotic pathway. In addition, we observed that the expression of cytoskeleton-associated proteins was significantly reduced in HD-iPSCs, implying that neuronal differentiation was also affected. Taken together, these results demonstrate that HD-iPSCs can provide a unique cellular disease model system to understand the pathogenesis and neurodegeneration mechanisms in HD, and the identified proteins from the present study may serve as potential targets for developing future HD therapeutics.

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NMR Spectroscopy-based Metabolomics of Drosophila Model of Huntington’s Disease Suggests Altered Cell Energetics

Journal of Proteome Research ◽

10.1021/acs.jproteome.7b00491 ◽

2017 ◽

Vol 16 (10) ◽

pp. 3863-3872 ◽

Cited By ~ 5

Author(s):

Virender Singh ◽

Raj Kumar Sharma ◽

Thamarailingam Athilingam ◽

Pradip Sinha ◽

Neeraj Sinha ◽

...

Keyword(s):

Nmr Spectroscopy ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Drosophila Model ◽

Altered Cell

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A drug candidate for Alzheimer’s and Huntington’s disease, PBT2, can be repurposed to render Neisseria gonorrhoeae susceptible to natural cationic antimicrobial peptides

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkab291 ◽

2021 ◽

Author(s):

Freda E -C Jen ◽

Ibrahim M El-Deeb ◽

Yaramah M Zalucki ◽

Jennifer L Edwards ◽

Mark J Walker ◽

...

Keyword(s):

Neisseria Gonorrhoeae ◽

Antimicrobial Peptides ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Proteomic Analysis ◽

Protein Misfolding ◽

Membrane Integrity ◽

Drug Candidate ◽

Cationic Antimicrobial Peptides ◽

Broth Microdilution Method

Abstract Background Neisseria gonorrhoeae is a Gram-negative bacterial pathogen that causes gonorrhoea. No vaccine is available to prevent gonorrhoea and the emergence of MDR N. gonorrhoeae strains represents an immediate public health threat. Objectives To evaluate whether PBT2/zinc may sensitize MDR N. gonorrhoeae to natural cationic antimicrobial peptides. Methods MDR strains that contain differing resistance mechanisms against numerous antibiotics were tested in MIC assays. MIC assays were performed using the broth microdilution method according to CLSI guidelines in a microtitre plate. Serially diluted LL-37 or PG-1 was tested in combination with a sub-inhibitory concentration of PBT2/zinc. Serially diluted tetracycline was also tested with sub-inhibitory concentrations of PBT2/zinc and LL-37. SWATH-MS proteomic analysis of N. gonorrhoeae treated with PBT2/zinc, LL-37 and/or tetracycline was performed to determine the mechanism(s) of N. gonorrhoeae susceptibility to antibiotics and peptides. Results Sub-inhibitory concentrations of LL-37 and PBT2/zinc synergized to render strain WHO-Z susceptible to tetracycline, whereas the killing effect of PG-1 and PBT2/zinc was additive. SWATH-MS proteomic analysis suggested that PBT2/zinc most likely leads to a loss of membrane integrity and increased protein misfolding and, in turn, results in bacterial death. Conclusions Here we show that PBT2, a candidate Alzheimer’s and Huntington’s disease drug, can be repurposed to render MDR N. gonorrhoeae more susceptible to the endogenous antimicrobial peptides LL-37 and PG-1. In the presence of LL-37, PBT2/zinc can synergize with tetracycline to restore tetracycline susceptibility to gonococci resistant to this antibiotic.

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Proteomic Analysis of Huntington’s Disease

Current Protein and Peptide Science ◽

10.2174/1389203721666201006160327 ◽

2020 ◽

Vol 21 (12) ◽

pp. 1218-1222

Author(s):

Shobhit Kumar ◽

Priyanka Singh ◽

Shrestha Sharma ◽

Javed Ali ◽

Sanjula Baboota ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Proteomic Analysis ◽

Autosomal Dominant ◽

Dominant Gene ◽

Polyglutamine Expansion ◽

X Ray ◽

Dna Mutation ◽

X Ray Crystallography ◽

Thinking Ability

: Huntington’s disease (HD) is a neurodegenerative disease that is genetically inherited through an autosomal dominant gene located on chromosome 4. HD is caused by DNA mutation (generally 37 or more repetition of CAG nucleotides) that leads to an excessive stretch of glutamine residues. However, the main pathogenesis pathway resulted by polyglutamine expansion in mutant HD is unknown. The characteristics of this disease mostly appear in adults. Patients who suffer from this disease have shown an inability to control physical movements, emotional problems, speech disturbance, dementia, loss of thinking ability and death occurs between 15-20 years from the time of symptomatic onset. This review article suggested that investigation of mutation in the HD gene can be done by proteomic analysis such as mass spectroscopy, gel electrophoresis, western blotting, chromatographic based technology, and X-ray crystallography. The primary aim of proteomics is to focus on the molecular changes occurring in HD, there by enhancing the effectiveness of treatment.

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