Intracellular clearance of toxic protein aggregates represents a promising therapeutic approach to treat protein-misfolding diseases such as Parkinson's and Huntington's diseases. Intracelluarly expressed antibody fragments or intrabodies can be used to bind specific intracellular targets. Addition of a non-traditional secretion signal sequence enables the intrabody to first bind its target inside the cell and then shuttle the bound target through the cell membrane, secreting it from the cell. We intracellularly expressed two different single chain antibody (scFv) fragments targeting either monomeric or oligomeric alpha-synuclein (a-syn), in a mammalian cell model that overexpresses a-syn. Two versions of each intrabody were studied, one with and one without the non-traditional secretion signal. The scFv targeting monomeric a-syn provided little or no reduction in toxicity induced by overexpression of a-syn, however binding and secretion of oligomeric a-syn totally reduced toxicity. Non-traditional intrabody secretion therefore represents an effective method to target and clear a variety of harmful intracellular species.