GRP78 Level Is Altered in the Brain, but Not in Plasma or Cerebrospinal Fluid in Parkinson’s Disease Patients

Abstract

Accumulation of misfolded proteins results in cellular stress, and is detected by specific sensors in the endoplasmic reticulum, collectively known as the unfolded protein response (UPR). It has been prominently proposed that the UPR is involved in the pathophysiology of Parkinson’s disease (PD). In the present study, the levels of the UPR proteins and mRNA transcripts were quantified in post mortem brain tissue from PD patients and matched controls. The level of a key mediator of the UPR pathway, glucose-regulated protein 78 (GRP78), was significantly decreased in temporal cortex and cingulate gyrus, whereas there were no significant changes in the caudate nucleus, prefrontal, or parietal cortex regions. On the other hand, GRP78 mRNA level was significantly increased in caudate nucleus, cingulate gyrus, prefrontal, and parietal cortex regions. GRP78 protein level was also measured in plasma and cerebrospinal fluid, but there were no differences in these levels between PD patients and control subjects. Furthermore, immunofluorescence labeling of the CD4 + T cells from PD patients showed that GRP78 protein is found in the cytoplasm. However, GRP78 level in PD patients was not significantly different from control subjects. Unlike the previous Lewy body dementia study, the present investigation reports reduced cortical protein, but increased transcript levels of GPR78 in PD. In summary, these data provide further evidence that GRP78 regulation is dysfunctional in the brains of PD patients.

A Weak Response to Endoplasmic Reticulum Stress Is Associated With Postoperative Organ Failure in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass

“…It is therefore not certain that GRP78 and UPR kinetics would be identical in a population without pathologies. However, it should be noted that the GRP78 plasma levels found before CPB and 24 h after CPB were very close to those recently described in a group of healthy volunteers, which probably makes our results quite extrapolable to other populations ( 42 ). Finally, we defined organ failure according to usual clinical criteria, but we did not use a standardized organ failure score such as the Sequential Organ Failure Assessment score.…”

Mutually exclusive dendritic arbors in C. elegans neurons share a common architecture and convergent molecular cues

“…It is likely that the IL2s also use the XBP-1-independent RIDD (regulated Ire1-dependent decay) pathway. The UPR regulates various aspects of remodeling in mammalian tissues [ 64 , 65 ]. Future work will be needed to determine the role of IRE-1 in dauer remodeling of other tissues, whether it is acting through the canonical UPR or XBP-1 independent mechanisms, and how these systemic stress responses influence dendrite morphology.…”

The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson’s Disease

“…However, all PD patients do not experience an increase in the UPR in tissues. Baek et al (2019) found that GRP78 mRNA levels are upregulated, but they also showed that the protein levels of GRP78 are decreased in several brain regions, including the cingulate gyrus in PD patients. Recently, similar findings suggested that both GRP78 and ATF4 protein levels are decreased in the SNpc in PD patients ( Esteves and Cardoso, 2020 ).…”