Proteasome function during aging in Drosophila
Item
-
Title
-
Proteasome function during aging in Drosophila
-
Identifier
-
d_2009_2013:2e947e24b423:11573
-
identifier
-
12111
-
Creator
-
Gao, Jie,
-
Contributor
-
Thomas Schmidt-Glenewinkel
-
Date
-
2012
-
Language
-
English
-
Publisher
-
City University of New York.
-
Subject
-
Biochemistry | Aging | Drosophila | Methuselah | Proteasome
-
Abstract
-
Aging is associated with dysfunction of protein homeostasis and increased protein damage caused by oxidative stress, but the detailed molecular mechanisms are unknown. The ubiquitin-proteasome pathway (UPP) is critical to the protein quality control system as it degrades a majority of intracellular proteins in eukaryotic cells. Age-related decline in proteasome function has been shown in a variety of mammalian tissues. However the role of UPP during the aging process still remains a puzzle. In this study, we compared the UPP function between two Drosophila melanogaster strains, the longevity mutant methuselah (mth) and the wild type w1118 at different ages, which would help answer this question.;The first part of the thesis evaluated the UPP function in mth and w1118 during the natual aging process and under oxidative stress condition. Mth encodes a GTP binding protein-coupled receptor (GPCR). The mth fly with a single Mth gene mutant has been shown to increase ∼35% lifespan, but the cellular role of Mth remained elusive. We are the first to report that mth displays lower proteasome activity, lower proteasome levels and lower ATP steady state levels at young ages, but relatively higher levels at old ages during normal aging, when compared with control strain w1118. Under oxidative stress conditions, proteasome activity remained nearly unchanged in w1118 after 5 days of treatment with 1% H2O2, but it was elevated in mth. Moreover, while both strains exhibited a gradual increase in ubiquitinated protein conjugates and aggregates during normal aging process, mth produced fewer conjugates and aggregates at the comparative ages than w1118. Under oxidative stress conditions, the levels of ubiquitinated conjugates and aggregates were elevated in both strains, but less were observed in mth. Together, these data suggest that mth exhibits higher proteasome plasticity and maintains a more efficient protein homeostasis, contributing to longer lifespan. We propose that maintaining a steady state protein turnover rate by the ubiquitin/proteasome pathway will delay the aging process.;In the second part of the thesis, we modulated different lifespans using non-genetic approach- Dietary Restriction (DR), which is the only intervention known so far to reliably increase lifespan in a variety of organisms. Currently, it is unclear that what effects aging and DR have on proteasome-mediated protein degradation. We compared the UPP function in three Drosophila strains, wild type Oregon R (OR), w1118 and longevity mutant mth under two diets - DR and ad libitum (AL). All three fly strains responded to DR with extended lifespan. In OR strain, DR significantly reduced proteasome activity in male and female flies at young ages (old ages not tested) and ATP level at all age groups in male flies. These data indicate higher proteasome activity and ATP level do not always lead to longer lifespan. In addition, DR significantly reduced age-related decline in proteasome activity, and ameliorated age-related increases in ubiquitinated protein in the wild type w1118. However, in mth, DR reduced proteasome activity and displayed a slightly higher level of ubiquitinated protein conjugates under both young and old ages. Our data indicate that DR has many beneficial effects towards the function of the UPP in wild type w1118, and that a preservation of the UPP may be a potential mechanism by which DR extend lifespan in w1118. But in longevity mutant mth, DR can not further ameliorate proteasome function, which suggests that other mechanisms might be responsible for the longer lifespan caused by DR. Cumulatively, these data have implications for understanding the effects of aging and DR on protein turnover and the mechanism of lifespan extension in longevity mutant mth..
-
Type
-
dissertation
-
Source
-
2009_2013.csv
-
degree
-
Ph.D.
-
Program
-
Biochemistry
