• Neurology Clinical Trials
• Dementias
• Extrapyramidal & Movement Disorders

• Neurology Clinical Trials
• Dementias
• Extrapyramidal & Movement Disorders
• Neurology

Even though they have distinct clinical, pathologic, and biochemical features, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease, and less commonly prion disease are all characterized by misfolded protein aggregation in the brain and fatal neuronal loss. The unfolded protein response (UPR) is emerging as a common player in all neurodegenerative diseases. Misfolded proteins in the endoplasmic reticulum (ER) trigger the dissociation of the ER chaperone GRP78/BiP from protein kinase ribonucleic acid– like ER kinase and other proteins, activating the UPR stress response. Initially the UPR is neuroprotective, but prolonged activation and failure to restore protein homeostasis can lead to neurodegeneration.

Evidence of UPR activation in both AD and PD suggests that the neurons are subjected to ER stress, but no studies have investigated the UPR in patients who have dementia with PD and AD pathology. The aim of this study, presented by Jean-Ha Baek, PhD, Karolinska Institute, Huddinge, Sweden, was to investigate changes in the UPR pathway in deceased subjects with PD with dementia (PDD) and dementia with Lewy bodies (DLB) in comparison with patients with AD and control subjects.

Postmortem brain tissue from 4 brain regions was provided by Brains for Dementia Research, United Kingdom, for evaluation (Table 1).

GRP78/BiP protein levels were quantified with western blot to measure the degree of UPR activation. Binding immunoglobulin protein (GRP78/BiP) expression patterns were assessed with immunohistochemistry.

Brain tissue from the cingulate gyrus of patients with PDD and those with DLB had a significant increase in the level of GRP78/BiP protein compared with tissue from patients with AD and control subjects (p=0.000 for all comparisons). GRP78/BiP protein expression in the parietal cortex was significantly decreased in brain tissue from patients with AD compared with control subjects (p=0.000) and significantly increased in tissue from patients with PDD compared with patients with AD (p=0.002) and in patients with DLB compared with those with AD (p=0.001). No significant differences were observed in GRP78/BiP levels in the prefrontal cortex and temporal cortex between any of the brain tissue sample groups.

Immunohistochemical studies detected GRP78/BiP protein in the cytoplasm of prefrontal cortex neurons in brain tissue from patients with AD, PDD, and DLB and controls. Although the labeling intensity was slightly increased in AD, PDD, and DLB patient samples compared with controls, the intensity was similar across the different disease groups.

This was the first study to investigate changes in the UPR pathway in deceased subjects with PDD and DLB in comparison with patients with AD and control subjects. Pearson correlation analysis found no association between changes in the GRP78/BiP protein level and Mini-Mental State Examination scores before death, rate of decline in Mini-Mental State Examination score, or global and regional pathologic scores for α-synuclein, plaques, and tangles. There was no correlation of Hoehn and Yahr scores with GRP78/BiP levels in a subset of subjects with PDD.

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