FIGURE 9.

Schematic of the process of aggresome formation and its progressive effects. The nucleus is shown in light blue, microtubules are in dark red, and polyQ72 is in green. During long term expression, polyQ-containing proteins are consistently expressed throughout the cytoplasm, and they gradually form an aggresome at the MTOC, which process is accompanied by polyQ fibrils covering the nuclear envelope. The aggresome formation is dependent on expression levels, as stronger promoters lead to higher incidence of aggresomes. The large volume occupied by aggresomes means they exert a strong steric interference on the mitotic machinery, resulting in perturbation of the formation of spindles and the alignment of chromosomes. The long term persistence of an aggresome leads to abnormal nuclei and a DNA damage response. At the molecular level (shown in the light pink box), long term accumulation of a juxtanuclear aggresome resulted in DSBs. This activates the DNA damage response, including the phosphorylation of H2AX and activation of p53-dependent cell cycle arrest. In summary, aggresomes generated by long term expression of aggregation-prone proteins have two major effects on the cells: DNA damage-induced cell cycle arrest and mitotic failure, with the latter caused by steric interaction between an aggresome and the mitotic machinery, including spindles and chromosomes.