Autophagy and the ubiquitin-proteasome system: Collaborators in neuroprotection

Abstract

Protein degradation is an essential cellular function that, when dysregulated or impaired, can lead to a wide variety of disease states. The two major intracellular protein degradation systems are the ubiquitin-proteasome system (UPS) and autophagy, a catabolic process that involves delivery of cellular components to the lysosome for degradation. While the UPS has garnered much attention as it relates to neurodegenerative disease, important links between autophagy and neurodegeneration have also become evident. Furthermore, recent studies have revealed interaction between the UPS and autophagy, suggesting a coordinated and complementary relationship between these degradation systems that becomes critical in times of cellular stress. Here we describe autophagy and review evidence implicating this system as an important player in the pathogenesis of neurodegenerative disease. We discuss the role of autophagy in neurodegeneration and review its neuroprotective functions as revealed by experimental manipulation in disease models. Finally, we explore potential parallels and connections between autophagy and the UPS, highlighting their collaborative roles in protecting against neurodegenerative disease.

Dual functions of autophagy in the response of breast tumor cells to radiation

“…* While autophagic flux by radiation alone is generally consistent with the data generated in other assays, the fact that suppression of p62 was similar for radiation alone and the combination of 1,25D 3 with radiation was unexpected. However, as p62 function is not limited solely to autophagy but is also associated with ubiquitin mediated protein degradation [31][32][33] it remains possible that our findings may reflect alternative roles of p62 in this system. *Although this representative experiment appears to indicate differences in the extent of p62 degradation between IR alone and 1,25D 3 + IR, densitometry analysis and pooling of the data from multiple western blots has determined that the level of p62 degradation is not significantly different between these treatments.…”

Autophagy as the main means of cytotoxicity by glucocorticoids in hematological malignancies

“…There are two main mechanisms by which the cells attempt to recover from aggregates of misfolded proteins: the proteasome, and in some cases through autophagy. 8 The combination of dexamethasone with the proteasome inhibitors has proven exceptionally successful in the demise of myeloma cells. 9 It seems rational that inhibition of the proteasome would lead to the activation of the autophagic program for the degradation of misfolded protein aggregates.…”

Protein repertoire impact of Ubiquitin–Proteasome System impairment: Insight into the protective role of beta-estradiol

“…Since UPS is more efficient than basal levels of macroautophagy, in the biological systems that have access to both pathways, proteasomes result to be the favored and dominating clearance route [2]. These scavenger systems target different proteins for degradation, such as proteins involved in the cell-cycle and abnormal proteins that, resulting from oxidative stress, disrupt normal cellular homeostasis [3,4]. Perturbations in both of these systems have been observed as cause or consequence in the pathogenesis of NDs [5,6].…”