Identification and Characterization of Multiple Distinct Proteasome Subpopulations in Striatal and Hippocampal Brain Regions

Morgan E. Nelson


The ubiquitin-proteasome pathway and proteolytic activities of the proteasome complex are responsible for multiple essential cellular processes. Modulation of proteasomal activities can alter the function of various brain regions, and possibly influence the neurodegenerative diseases in a brain region-dependent manner. The proteasome heterogeneity that exists in different brain regions could be a contributing factor to the different sensitivities of these regions reported in neurodegenerative diseases. Utilizing in vitro and in vivo approaches, we provide direct evidence of distinct proteasome subpopulations in different brain regions. Results obtained from this study suggest that proteasome subpopulations differ in their molecular compositions, and in the proteolytic activities excised from different brain regions. Moreover, the proteasome subpopulations identified in brain regions are different from the proteasome subpopulations studied in other tissues. Utilizing iodixanol gradient and fluorescent assay protocols, we found that there are two distinct forms of proteasome complexes with different levels of catalytic activities. Importantly, proteasome subpopulations display different levels of responses to the proteasome inhibitors. An extensive Western blot analysis suggested that the distinct proteasome assembly may be a contributing factor to variations in proteolytic activities. Besides molecular composition, post-translational modifications and specific protein partners may contribute to these differences. This data suggests the possibility of two proteasome subpopulations. The identification of different proteasome subpopulations in brain regions provides mechanistic insights for the temporal and spatial responses of proteasome in various regions of brain. This study identifies proteasome components that may serve as novel therapeutic targets in neurodegenerative diseases.