Apparent relationship between aggregate size and “toxic surface area” deserves further investigation, especially with regard to intracellular amyloidogenic proteins in compound aggregated states such as inclusion bodies and aggresomes. Alternatively, we cannot exclude the possibility that scFv-6E may Mechlorethamine hydrochloride stabilize a recently described oligomeric species having fibrillar features, although the existence of such oligomers has yet to be correlated with cytopathology. On this subject, it is noteworthy that the fibrillogenesis of ataxin-3 is initiated by a monomeric nucleus and grows by monomer addition rather than through oligomers in solution, and a similar mechanism may hold true for mutant httex1 as well. Paradoxically, viable cells containing intracellular aggregates significantly outnumbered those that died with aggregates in our cytotoxicity experiments, demonstrating that aggregates per se are not instantly toxic to ST14A striatal-derived cells. This observation is consistent with previous reports demonstrating a penchant for inclusion bodies to be protective, a fact which has called into question how visible protein Labetalol hydrochloride aggregation can be associated with neuropathological abnormalities even though aggregates themselves are not universally predictive of neurodegeneration. Using intrabodies to alter the kinetics of amyloidogenesis, our data illustrates that the overall speed of aggregate formation bears more relevance to the severity of intracellular dysfunction than whether or not inclusions are present at any given time point. Indeed, time-lapse microscopy in a PC12 cell model of HD has revealed that aggregation tends to occur rapidly in cells that die with inclusions and much slower in cells that survive with inclusions. We conclude that the rate of aggregation likely influences the magnitude of cellular dysfunction elicited by aggregation, such as oxidative stress in the case of mutant httex1. Hence, escalating the formation of httex1 aggregates with a fibrilspecific intrabody heightens oxidative stress and results in greater toxicity in ST14A striatal cells. In contrast, suppressing aggregation with an intrabody that shields the amyloidogenic N-terminus of mutant huntingtin in fact reduces oxidative stress and toxicity in these cells. Importantly, oxidative stress complements several prevailing models of HD pathogenesis, including excitoxicity, mitochondrial dysfunction, and inflammation.