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.
Highlights
Parkinson’s disease (PD) is one of the most common neurodegenerative disease affecting 1–2% of the population over 60 years of age (Dorsey and Bloem, 2018)
Caudate nucleus was selected for its involvement in motor function in PD; prefrontal cortex was selected for its proposed role in executive function and cognition; cingulate gyrus was selected for the early development of pathology encountered in this region, while parietal cortex was selected because of its pathological predominance in Alzheimer’s disease (AD) as opposed to PD; temporal cortex was chosen due to its suggested role in auditory processing and language
There was a significant decrease in the level of glucose-regulated protein 78 (GRP78) protein in PD patients compared to control subjects in temporal cortex (P = 0.0007) and cingulate gyrus (P = 0.001, Figure 1A)
Summary
Parkinson’s disease (PD) is one of the most common neurodegenerative disease affecting 1–2% of the population over 60 years of age (Dorsey and Bloem, 2018). PD is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta and deposits of intracellular protein inclusions called Lewy bodies, where aggregates of misfolded α-synuclein (α-syn) are the major components (Spillantini et al, 1997). These causative factors for PD have been known for many years and extensive research have been done to halt the disease progression, at present, there are no disease modifying therapies available for PD. Current treatments only restore dopamine neurotransmission and reduce symptoms, but do not stop or slow down the disease progression.
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