There is currently no cure for neurodegenerative disease or the underlying burden of protein aggregation that is associated with symptom development. A novel approach to combat this accumulation of misfolded protein species is surprisingly found in a protein disaggregase in yeast, the heat shock protein Hsp104. To investigate whether Hsp104 can be introduced into an animal system and harnessed to attack disease-associated protein inclusions, we created a transgenic Drosophila model expressing Hsp104 and investigated whether this would mitigate toxicity and alter the load of protein accumulations. We found that Hsp104 indeed suppressed toxicity of a disease-associated protein fragment containing an expanded polyglutamine tract. However, we found that Hsp104 worsened toxicity of the full-length pathogenic polyglutamine protein, and this coincided with increased accumulation of amyloid inclusions. This aberrant activity of Hsp104 depended on intact domains in the non-polyglutamine stretches of the protein, and this negative interaction could be prevented by mutation to these neighboring domains. These results indicate that knowing the precise protein state of a disease environment is critical in evaluating potential therapeutics. Moreover, we sequentially activated Hsp104 after the onset of protein aggregation and start of tissue degeneration, to find that Hsp104, but not Hsp70, significantly suppressed progressive degeneration. Thus, the unique ability of Hsp104 to tackle pre-existing amyloid conformers may offer a novel opportunity to reverse disease progression once underway.