Aging perturbs 26S proteasome assembly inDrosophila melanogaster

Abstract

Aging is associated with loss of quality control in protein turnover. The ubiquitin-proteasome pathway is critical to this quality control process as it degrades mutated and damaged proteins. We identified a unique aging-dependent mechanism that contributes to proteasome dysfunction in Drosophila melanogaster. Our studies are the first to show that the major proteasome form in old (43-47 days old) female and male flies is the weakly active 20S core particle, while in younger (1-32 days old) flies highly active 26S proteasomes are preponderant. Old (43-47 days) flies of both genders also exhibit a decline (approximately 50%) in ATP levels, which is relevant to 26S proteasomes, as their assembly is ATP-dependent. The steep declines in 26S proteasome and ATP levels were observed at an age (43-47 days) when the flies exhibited a marked drop in locomotor performance, attesting that these are "old age" events. Remarkably, treatment with a proteasome inhibitor increases ubiquitinated protein levels and shortens the life span of old but not young flies. In conclusion, our data reveal a previously unknown mechanism that perturbs proteasome activity in "old-age" female and male Drosophila most likely depriving them of the ability to effectively cope with proteotoxic damages caused by environmental and/or genetic factors.

Proteasome regulation, plant growth and stress tolerance

“…33 This study shows that 26SP levels decline during the aging process while 20SP biogenesis increases. A similar trend, i.e., decline in 26SP levels combined with increase in 20SP levels, was suggested by a proteomics study of potato tuber aging.…”

Inhibition of Proteasome Activity Induces Formation of Alternative Proteasome Complexes

“…The reduction of 26S proteasome function is a physiologically relevant situation. Impairment of 26S proteasome activity has been reported for aging, (66,67), neurodegeneration (68), and oxidative stress (69). In these studies, however, formation of alternative proteasome complexes as part of the cellular response to impaired 26S proteasome function was not investigated.…”

Regulatory Role of Proteasome in Determination of Platelet Life Span

“…Proteasome enzymic function is known to decline with cell aging (42,43), which would lead to accumulation of pro-apoptotic proteins like Bax in platelets. Thus, progressive attenuation in activities of either Bcl-X L (7,8) or proteasome in aging cells would result in unrestrained activity of pro-apoptotic Bax/Bak, eventually leading to platelet cell death and phagocytic clearance.…”