4.7 Article

Aging perturbs 26S proteasome assembly in Drosophila melanogaster

Journal

FASEB JOURNAL
Volume 21, Issue 11, Pages 2672-2682

Publisher

FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.06-6751com

Keywords

ubiquitin; protein degradation; 26S/20S proteasomes; ATP depletion; fly aging

Funding

  1. NCRR NIH HHS [RR03037, G12 RR003037] Funding Source: Medline
  2. NIA NIH HHS [R01 AG028847] Funding Source: Medline
  3. NIGMS NIH HHS [GM60654, S06 GM060654] Funding Source: Medline
  4. NINDS NIH HHS [NS41073, U54 NS041073] Funding Source: Medline

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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 ( similar to 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.

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