Endoplasmic Reticulum Stress Is Important for the Manifestations of α-SynucleinopathyIn Vivo

Abstract

Accumulation of misfolded α-synuclein (αS) is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other α-synucleinopathies. However, how αS 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 α-synucleinopathy. Using the A53T mutant human αS transgenic (A53TαS Tg) mouse model of α-synucleinopathy, we show that disease onset in the αS Tg model is coincident with induction of ER chaperone in neurons exhibiting αS pathology. However, the neuronal ER chaperone induction was not accompanied by the activation of phospho-eIF2α, indicating that α-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 αS monomers and aggregates. Significantly, human PD cases also exhibit higher relative levels of ER/M αS than the control cases. Moreover, αS interacts with ER chaperones and overexpression of αS sensitizes neuronal cells to ERS-induced toxicity, suggesting that αS 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 A53TαS Tg mouse model and the Adeno-associated Virus-transduced rat model of A53T α S-dependent dopaminergic neurodegeneration. Our data indicate that the accumulation αS within ER leads to chronic ER stress conditions that contribute to neurodegeneration in α-synucleinopathies. Attenuating chronic ERS could be an effective therapy for PD and other α-synucleinopathies.

Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain

“…Prior studies have shown that Asyn localizes to Rab1 ϩ membranes, alters membrane trafficking, and modulates ER stress signaling (27,36). Given that WNV manipulates ER stress signaling (34,37,38), we hypothesized that Asyn expression modulates ER stress signaling following viral infection and that, in the absence of Asyn, ER stress signals are increased in support of WNV replication.…”

“…We found that virus-induced Asyn localized with viral envelope proteins and significantly increased the localization with Rab1 ϩ membranes. Previous work has shown that Asyn localization to Rab1 ϩ membranes alters membrane transport from the ER to the Golgi body, resulting in changes in ER stress signals and ER remodeling within the neuron (27,36). In general, positive-stranded RNA viruses are dependent on membrane remodeling to support viral replication.…”

GRP78 clustering at the cell surface of neurons transduces the action of exogenous alpha-synuclein

“…GRP78 is a major ER chaperone protein 23 involved in the UPR, which is frequently altered in neurodegenerative diseases, 32 known to interact with Syn in the ER in stress conditions. 33,34 We provided evidence that the binding of extracellular Syns to GRP78 occurs at the cell surface and leads to its clustering in discrete membrane domains, possibly as a consequence of inhibition of its lateral movement along the plasma membrane, and of its decreased recycling. Alternatively, Syn might induce clustering of GRP78 at the cell surface through changes in membrane composition, curvature and integrity.…”

Roles of Endoplasmic Reticulum Stress in Neurodegenerative Diseases

“…Understanding the pathways by which misfolded proteins cause neurodegeneration is essential for developing efficient treatments for neurodegenerative disorders. On the other hand, although targeting ER stress may be beneficial for patients with neurodegenerative disorders, new therapeutic agents must be carefully screened and tested in appropriate disease models to avoid possible adverse effects [5,21,22,34].…”

“…Inhibition of phosphorylation of eIF2α protected the A53T α-synuclein over expressing cells from cell death, suggesting that ER stress response was shifting the balance towards apoptosis [33]. Recent studies further indicate that the accumulation of α-synuclein within ER leads to chronic ER stress conditions that contribute to neurodegeneration in PD and other alpha-synucleinopathies [34,35]. Similarly, evidences have indicated that protein products of genes mutated in PD, such as ubiquitin carboxyl-terminal esterase L1 (UCHL1), leucine-rich repeat kinase 2 (LRRK2), Parkinson protein 2 (Parkin), PTENinduced kinase 1 (PINK1) and DJ-1, play a role in regulating protein stability and ER stress response [22,31,32].…”