Accumulation of misfolded alpha-synuclein (alpha S) is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other alpha-synucleinopathies. However, how alpha S causes neurodegeneration is unresolved. Because cellular accumulation of misfolded proteins can lead to endoplasmic reticulum stress/unfolded protein response (ERS/UPR), chronic ERS could contribute to neurodegeneration in alpha-synucleinopathy. Using the A53T mutant human alpha S transgenic (A53T alpha STg) mouse model of alpha-synucleinopathy, we show that disease onset in the alpha S Tg model is coincident with induction of ER chaperones in neurons exhibiting alpha S pathology. However, the neuronal ER chaperone induction was not accompanied by the activation of phospho-eIF2 alpha, indicating that alpha-synucleinopathy is associated with abnormal UPR that could promote cell death. Induction of ERS/UPR was associated with increased levels of ER/microsomal (ER/M) associated alpha S monomers and aggregates. Significantly, human PD cases also exhibit higher relative levels of ER/M alpha S than the control cases. Moreover, alpha S interacts with ER chaperones and overexpression of alpha S sensitizes neuronal cells to ERS-induced toxicity, suggesting that alpha S may have direct impact on ER function. This view is supported by the presence of ERS-activated caspase-12 and the accumulation of ER-associated polyubiquitin. More important, treatment with Salubrinal, an anti-ERS compound, significantly attenuates disease manifestations in both the A53T alpha S Tg mouse model and the adeno-associated virus-transduced rat model of A53T alpha S-dependent dopaminergic neurodegeneration. Our data indicate that the accumulation alpha S within ER leads to chronic ER stress conditions that contribute to neurodegeneration in alpha-synucleinopathies. Attenuating chronic ERS could be an effective therapy for PD and other alpha-synucleinopathies.