Ubiquitin/Proteasome and Autophagy/Lysosome Pathways: Comparison and Role in Neurodegeneration

Abstract

Neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as amyotrophic lateral sclerosis, are a heterogeneous group of clinical diseases that are characterized by the selective loss of neurons in specific regions of the CNS. Despite their variability they have similar features including the accumulation of misfolded proteins that eventually develop into inclusion bodies. Whether these protein deposits are pathogenic or represent a coping mechanism to prolong survival of the affected neurons is a hotly debated issue. One important point to consider is that these protein deposits are indicative of a disease-state as they are not prevalent in healthy cells. Ubiquitinated proteins are major components of these proteinaceous cytoplasmic or nuclear inclusions suggesting that impaired proteasome activity and the ubiquitination machinery may be main players in this process. Emerging data revealed that autophagosomes are also components of inclusion bodies, implicating the autophagy/lysosome pathway in neurodegenerative disorders as well. Herein, we compare some of the most important characteristics of these two pathways for intracellular protein degradation and discuss their potential role in neurodegeneration. When the proteasome is impaired, it is possible that autophagy may be the alternate pathway for clearing out aggregated ubiquitinated proteins. The question emerges if this potential “survival” mechanism can be explored as a strategy to overcome the most common feature shared by various neurodegenerative disorders, i.e., protein aggregation manifested as inclusion bodies. One potential drawback is that degradation through autophagy seems to be a “bulky,” nonspecific process. A thorough knowledge of the mechanisms involved in the targeting of substrates to autophagy will provide clues to the putative specificity of this pathway so that its ectopic manipulation will target only abnormal protein aggregates and not critical intracellular components, the removal of which may cause cell death.