Induction of the unfolded protein response by α-synuclein in experimental models of Parkinson’s disease

Abstract

J. Neurochem. (2011) 116, 588–605. Abstract Accumulation of misfolded proteins in the endoplasmic reticulum (ER) is the main event leading to the induction of the ER stress‐related unfolded protein response (UPR). Recent postmortem evaluation, showing that the UPR pathway is activated in nigral dopaminergic neurons bearing α‐synuclein inclusions in the brain of Parkinson’s disease (PD) patients, suggests that the activation of the UPR may be induced by the accumulation of α‐synuclein. In this study, we show that the misfolded protein‐sensor/UPR activator glucose‐regulated protein 78/immunoglobulin heavy chain‐binding protein was bound to α‐synuclein and was increased in ‘in vitro’ and ‘in vivo’ models showing aggregated α‐synuclein accumulation. Moreover, α‐synuclein accumulation induced the expression of the UPR‐related activating transcription factor 4/cAMP‐responsive element‐2. These findings indicate that activation of the UPR pathway in the PD brain is associated with α‐synuclein accumulation occurring in part within the ER.

Heat Shock 70-kDa Protein 5 (Hspa5) Is Essential for Pronephros Formation by Mediating Retinoic Acid Signaling

“…7B). It is worth noting that strong nucleus-localized HSPA5 signals were detected in SH-SH5Y cells, consistent with a previous study (51). Collectively, we have provided evidence to support that HSPA5 is required to maintain the RAR␣ expression at the protein level that may contribute to the inhibition of RA signaling.…”

α-synuclein and synapsin III cooperatively regulate synaptic function in dopamine neurons

“…In addition, we have shown that glucose deprivation is also able to induce α-syn aggregation within the endoplasmic reticulum (ER). The binding of α-syn aggregates to the ER-stress sensor glucose regulated protein 78 (GRP78) then induces the unfolded protein response (UPR) (Bellucci et al, 2011b), an ER-stress response that is activated in Parkinson's-disease-affected brains. Prolonged activation of the UPR blocks ER-Golgi trafficking.…”

ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

“…Remarkably, treating mutant A53T mice with salubrinal attenuated the onset of motor dysfunction, although this treatment was not sufficient to protect dopaminergic neurons following adeno-associated (AAV) distribution of αSynuclein mutant A53T in rats [72]. Other UPR mediators that were shown to be upregulated in the brain of α-synuclein transgenic mice also include BiP, XBP1, CHOP, and ATF4 [72][73][74]. Interestingly, ER stress induction after tunicamycin treatment was sufficient to increase α-synuclein aggregation, indicating a causal relation in disease pathogenesis and also sustaining that UPR dysfunction may act as a positive feedback for aggregation and cellular death [75].…”

“…Consistently, α-synucleinopathy in mice is coincident with induction of ER stress and leads to abnormal UPR signal, thus leading to cell death pathway activation and a fraction of monomers and aggregates of α-synuclein locates inside the ER, where it is found in association with ER chaperones [70,71]. Remarkably, treating mutant A53T mice with salubrinal attenuated the onset of motor dysfunction, although this treatment was not sufficient to protect dopaminergic neurons following adeno-associated (AAV) distribution of αSynuclein mutant A53T in rats [72]. Other UPR mediators that were shown to be upregulated in the brain of α-synuclein transgenic mice also include BiP, XBP1, CHOP, and ATF4 [72][73][74].…”