Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by tremor at rest, postural instability, bradykinesia, and rigidity. Mutations in ATP13A2 have been linked to the development of Kufor-Rakeb syndrome (KRS), a juvenile-onset form of parkinsonism with dementia. The ATP13A2gene is alternatively spliced to produce three Atp13a2 protein isoforms. However, little is known about the function of Atp13a2 in the cell or how mutations in the gene cause disease. It has been reported that wild type (wt) proteins localize to lysosomes while mutant Atp13a2Isoform-1 proteins are retained in the endoplasmic reticulum (ER) and rapidly degraded by the proteasome. These findings suggest mutant Atp13a2Isoform-1 proteins are eliminated by the ER-associated degradation (ERAD) pathway, the process by which misfolded proteins are retro-translocated from the ER to the cytoplasm for degradation by the proteasome, although direct evidence for this was not demonstrated. We approached this question by examining protein turnover after disrupting specific components of the ERAD pathway. Interference of ERAD by either inhibition of the proteasome, or expression of a dominant negative p97/VCP QQ mutant, or knockdown of erasin, slowed the turnover of mutant Atp13a2Isoform-1proteins. Furthermore, immunoprecipitation assays revealed Atp13a2 proteins are ubiquitinated, as expected. Functional studies in HeLa cells indicated that overexpression of the wild type Atp13a2Isoform-1 protein is cytoprotective against agents that cause ER stress, manganese toxicity, and starvation. Similar studies of the Atp13a2Isoform-3 proteins revealed surprising differences. In contrast to the Atp13a2Isoform-1 protein, wild type Atp13a2Isoform-3 was found to localize to the ER, be rapidly degraded by the proteasome, and its overexpression was found to be cytotoxic. These results provide new insight into functional differences between wild type and mutant Atp13a2 proteins, which are likely to be important in understanding the pathogenicity of Atp13a2 proteins in PD.