Metabolic deregulation associated with aging modulates protein aggregation in the yeast model of Huntington's disease

被引：2

作者：

Pradhan, Sai Sanwid ^{[1
]}

Swaroop, R. Sai ^{[1
]}

Kanikaram, Sai Phalguna ^{[1
]}

Darshan, V. M. Datta ^{[1
]}

Pargaonkar, Ashish ^{[2
]}

Dandamudi, Rajesh Babu ^{[3
]}

Sivaramakrishnan, Venketesh ^{[1
]}

机构：

[1] Sri Sathya Sai Inst Higher Learning, Dept Biosci, Dis Biol Lab, Anantapur, Andhra Pradesh, India

[2] Agilent Technol Ltd, Applicat Div, Bengaluru, Karnataka, India

[3] Phenomenex India, Hyderabad, Telangana, India

来源：

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS | 2024年 / 42卷 / 19期

关键词：

Huntingtin; Huntington's disease; metabolomics; neurodegeneration; aging; protein aggregation; chaperon; R6/1 MOUSE MODEL; AGE-OF-ONSET; OXIDATIVE STRESS; NITRIC-OXIDE; POLYGLUTAMINE AGGREGATION; GLUCOSE-METABOLISM; REPEAT LENGTH; HUMAN BRAIN; EXPRESSION; MICE;

D O I：

10.1080/07391102.2023.2257322

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Huntington's disease is associated with increased CAG repeat resulting in an expanded polyglutamine tract in the protein Huntingtin (HTT) leading to its aggregation resulting in neurodegeneration. Previous studies have shown that N-terminal HTT with 46Q aggregated in the stationary phase but not the logarithmic phase in the yeast model of HD. We carried out a metabolomic analysis of logarithmic and stationary phase yeast model of HD expressing different polyQ lengths attached to N-terminal HTT tagged with enhanced green fluorescent protein (EGFP). The results show significant changes in the metabolic profile and deregulated pathways in stationary phase cells compared to logarithmic phase cells. Comparison of metabolic pathways obtained from logarithmic phase 46Q versus 25Q with those obtained for presymptomatic HD patients from our previous study and drosophila model of HD showed considerable overlap. The arginine biosynthesis pathway emerged as one of the key pathways that is common in stationary phase yeast compared to logarithmic phase and HD patients. Treatment of yeast with arginine led to a significant decrease, while transfer to arginine drop-out media led to a significant increase in the size of protein aggregates in both logarithmic and stationary phase yeast model of HD. Knockout of arginine transporters in the endoplasmic reticulum and vacuole led to a significant decrease in mutant HTT aggregation. Overall our results highlight arginine as a critical metabolite that modulates the aggregation of mutant HTT and disease progression in HD.Communicated by Ramaswamy H. Sarma

引用

页码：10521 / 10538

页数：18

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