Huntingtin and mutant SOD1 form aggregate structures with distinct molecular properties in human cells.

Expression of many proteins associated with neurodegenerative disease results in the appearance of misfolded species that readily adopt alternate folded states. In vivo, these appear as punctated subcellular structures typically referred to as aggregates or inclusion bodies. Whereas groupings of these distinct proteins into a common morphological class have been useful conceptually, there is some suggestion that aggregates are not homogeneous and can exhibit a range of biological properties. In this study, we use dynamic imaging analysis of living cells to compare the aggregation and growth properties of mutant huntingtin with polyglutamine expansions or mutant SOD1 (G85R/G93A) to examine the formation of aggregate structures and interactions with other cellular proteins. Using a dual conditional expression system for sequential expression of fluorescence-tagged proteins, we show that mutant huntingtin forms multiple intracellular cytoplasmic and nuclear structures composed of a dense core inaccessible to nascent polypeptides surrounded by a surface that stably sequesters certain transcription factors and interacts transiently with molecular chaperones. In contrast, mutant SOD1 (G85R/G93A) forms a distinct aggregate structure that is porous, through which nascent proteins diffuse. These results reveal that protein aggregates do not correspond to a single common class of subcellular structures, and rather that there may be a wide range of aggregate structures, perhaps each corresponding to the specific disease-associated protein with distinct consequences on the biochemical state of the cell.