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Abstract

The formation of insoluble protein aggregates is a pathological event associated with many neurodegenerative disorders. Accruing evidence demonstrates that protein aggregation is not restricted to disease processes and also occurs during normal aging affecting several hundred proteins. Until now, little is known concerning the tissue-specific mechanisms controlling age-dependent protein aggregation. In the present study, we investigated age-dependent protein aggregation during impairment of macroautophagy in two different muscle cell types in C. elegans: non-striated muscles in the pharynx and striated body-wall muscles. Surprisingly, we found a striking reduction in protein aggregation in the pharyngeal muscles upon macroautophagy impairment. This unexpected response was tissue-specific as impaired macroautophagy accelerated protein aggregation in the body-wall muscles. We provide evidence for a novel safeguard against protein aggregation (SAPA) triggered by protein-quality control failure that targets specifically newly synthesized aggregation-prone proteins in the pharyngeal muscle cells. We show that SAPA relies on macroautophagy-independent lysosomal degradation and involves components normally up-regulated in response to intracellular pathogens affecting the digestive tract.