| First Author | Colla E | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 10 | Pages | 3306-20 |
| PubMed ID | 22399753 | Mgi Jnum | J:182734 |
| Mgi Id | MGI:5316524 | Doi | 10.1523/JNEUROSCI.5367-11.2012 |
| Citation | Colla E, et al. (2012) Endoplasmic reticulum stress is important for the manifestations of alpha-synucleinopathy in vivo. J Neurosci 32(10):3306-20 |
| abstractText | Accumulation of misfolded alpha-synuclein (alphaS) is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other alpha-synucleinopathies. However, how alphaS 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 alphaS transgenic (A53TalphaS Tg) mouse model of alpha-synucleinopathy, we show that disease onset in the alphaS Tg model is coincident with induction of ER chaperones in neurons exhibiting alphaS pathology. However, the neuronal ER chaperone induction was not accompanied by the activation of phospho-eIF2alpha, 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 alphaS monomers and aggregates. Significantly, human PD cases also exhibit higher relative levels of ER/M alphaS than the control cases. Moreover, alphaS interacts with ER chaperones and overexpression of alphaS sensitizes neuronal cells to ERS-induced toxicity, suggesting that alphaS 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 A53TalphaS Tg mouse model and the adeno-associated virus-transduced rat model of A53TalphaS-dependent dopaminergic neurodegeneration. Our data indicate that the accumulation alphaS 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. |
