Intracellular protein degradation decreases with age, altering the important balance between
protein synthesis and breakdown. Slowly,
protein accumulation events increase causing axonopathy, synaptic deterioration, and subsequent cell death. As toxic species accumulate, autophagy-lysosomal protein degradation pathways are activated. Responses include autophagic vacuoles that degrade damaged cellular components and long-lived
proteins, as well as enhanced levels of lysosomal
hydrolases. Although such changes correlate with neuronal
atrophy in age-related
neurodegenerative disorders and in related models of
protein accumulation, the autophagic/lysosomal responses appear to be compensatory reactions. Recent studies indicate that
protein oligomerization/ aggregation induces autophagy and activates lysosomal protein degradation in an attempt to clear toxic accumulations. Such compensatory responses may delay cell death and account for the gradual nature of
protein deposition pathology that can extend over months/years in model systems and years/decades in the human diseases. Correspondingly, enhancement of compensatory pathways shifts the balance from pathogenesis to protection. Positive modulation of protein degradation processes represents a strategy to promote clearance of toxic accumulations and to slow the synaptopathogenesis and associated
cognitive decline in aging-related
dementias.