Altered unfolded protein response and proteasome impairment in pseudoexfoliation pathogenesis

Bushra Hayat; Biswajit Padhy; Pranjya Paramita Mohanty; Debasmita Pankaj Alone

doi:10.1016/j.exer.2019.02.004

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Altered unfolded protein response and proteasome impairment in pseudoexfoliation pathogenesis

Journal article

Peer reviewed

Altered unfolded protein response and proteasome impairment in pseudoexfoliation pathogenesis

Bushra Hayat, Biswajit Padhy, Pranjya Paramita Mohanty and Debasmita Pankaj Alone

Experimental eye research, Vol.181, pp.197-207

04/01/2019

DOI: 10.1016/j.exer.2019.02.004

PMID: 30738879

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Abstract

Pseudoexfoliation (PEX), an ocular disorder involving deposition of proteinaceous fibrils on the surface of anterior eye tissues, is a major contributing factor to worldwide glaucoma. Excessive production and accumulation of fibrillar materials in PEX could be an indication of proteostasis imbalance. This study aims at investigating the differential expression of various genes involved in unfolded protein response and ubiquitin proteasome pathway in pseudoexfoliation (PEX) patients compared to non-PEX controls using lens capsule tissue as the study material. The custom RT(2 )Profiler PCR array was used to identify a set of stress-related candidate genes that were differentially expressed in PEX. The expression of the highly deregulated genes was validated by qRT-PCR and subsequently their protein expression was checked through immunoblotting and immunostaining. Proteasome-Glo based assay and TUNEL assay were employed to detect specific proteasomal activity and apoptotic activity, respectively in the study subjects. Increased ER stress markers, Synoviolinl, Eukaryotic initiation factor 2-alpha kinase 3, DnaJ (Hsp40) homolog, subfamily B, member 11, Caspase 12, Heat shock 70 kDa protein 5, Heat shock 60 kDa protein 1 and Calnexin were observed in the lens capsule of PEX individuals compared to age-matched controls. On the other hand, increased ubiquitin B mRNA expression followed by significant downregulation of proteasome subunits; 26 S proteasome non-ATPase regulatory subunit 1, and proteasome subunit alpha-type 5 was found in pseudoexfoliation syndrome (PEXS) individuals. Decrease in chymotrypsin-like proteasome activity and increased apoptosis were also observed in PEX subjects. The present findings provide evidence for alterations in endoplasmic reticulum-related stress response and ubiquitin proteasome function in lens capsule of PEX individuals. Altogether, our study has identified deregulated expression of candidate genes in ER-UPR pathway and implicates proteasome impairment as a causative factor in PEX pathogenesis.

Life Sciences & Biomedicine

Ophthalmology

Science & Technology

Details

Title: Subtitle: Altered unfolded protein response and proteasome impairment in pseudoexfoliation pathogenesis
Creators: Bushra Hayat - National Institute of Science Education and Research
Biswajit Padhy - National Institute of Science Education and Research
Pranjya Paramita Mohanty - Sri Sri Borda Hosp, Bhubaneswar 751002, Odisha, India
Debasmita Pankaj Alone - National Institute of Science Education and Research
Resource Type: Journal article
Publication Details: Experimental eye research, Vol.181, pp.197-207
DOI: 10.1016/j.exer.2019.02.004
PMID: 30738879
ISSN: 0014-4835
eISSN: 1096-0007
Publisher: Elsevier
Number of pages: 11
Grant note: 27(0317)/16/EMR-II / Council of Scientific and Industrial Research (India); Council of Scientific & Industrial Research (CSIR) - India National Institute of Science Education and Research, an autonomous organization under Department of Atomic Energy, Government of India
Language: English
Date published: 04/01/2019
Academic Unit: Internal Medicine
Record Identifier: 9985157526302771

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