Alternatively, we cannot exclude the possibility that scFv-6E may 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, Yunaconitine 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 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, as evidenced by the ability of the mitochondrial poison 3-nitropropionic acid to mimic striatum-specific HD-like motor defects. Conversely, ataxin-3 is implicated in the regulation of endoplasmic reticulum -associated degradation ; thus, it is tempting to speculate that stimulating the aggregation of ataxin-3 might exacerbate ER stress-related dysfunction. In total, our findings support the general notion that polyglutamine aggregate-formation contributes to neurodegeneration by sensitizing cells to physiologic or environmental stress. In this regard, blocking or slowing aggregation elicits a strong cytoprotective effect in our study. These implications may hold importance for other protein misfolding diseases such as Amyotrophic Lateral Sclerosis, tauopathies, and Parkinson��s, Alzheimer��s, and prion disorders. As flight animals and grazers the wild ancestors of modern horses were naturally selected for speed and the ability to traverse long distances. Since horses were domesticated on the Eurasian steppe some 6,000 years ago they have been selected for strength, speed and endurance-exercise traits. This process has been uniquely augmented in Thoroughbred horses, which for four Pancuronium dibromide centuries have been subject to intense artificial selection for system-wide structural and functional adaptations that contribute to athletic performance phenotypes.