Synphilin-1 has previously been identified as an interaction partner of α-Synuclein (αSyn), a primary constituent of neurodegenerative disease-linked Lewy bodies. In this study, the repercussions of a disrupted glyoxalase system and aldose reductase function on Synphilin-1 inclusion formation characteristics and cell growth were investigated. To this end, either fluorescent dsRed-tagged or non-tagged human  SNCAIP , which encodes the Synphilin-1 protein, was expressed in  Saccharomyces cerevisiae  and  Schizosaccharomyces pombe  yeast strains devoid of enzymes Glo1, Glo2, and Gre3. Presented data shows that lack of Glo2 and Gre3 activity in  S. cerevisiae  increases the formation of large Synphilin-1 inclusions. This correlates with enhanced oxidative stress levels and an inhibitory effect on exponential growth, which is most likely caused by deregulation of autophagic degradation capacity, due to excessive Synphilin-1 aggresome build-up. These findings illustrate the detrimental impact of increased oxidation and glycation on Synphilin-1 inclusion formation. Similarly, polar-localised inclusions were observed in wild-type  S. pombe  cells and strains deleted for either  glo1 +   or  glo2 +  . Contrary to  S. cerevisiae , however, no growth defects were observed upon expression of  SNCAIP . Altogether, our findings show the relevance of yeasts, especially  S. cerevisiae , as complementary models to unravel mechanisms contributing to Synphilin-1 pathology in the context of neurodegenerative diseases.