Abstract
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are neurodegenerative disorders with a severe medical and social impact. Further insights from clinical and scientific studies are essential to develop effective therapies. Various stresses on the endoplasmic reticulum (ER) cause unfolded/misfolded proteins to aggregate, initiating unfolded protein responses (UPR), one of which is the induction of neuronal cell death. Some of the pathogenic factors for AD and PD are associated with UPR. ER molecules such as ubiquitin ligases (E3s) and chaperones are also produced during UPR to degrade and refold aberrant proteins that accumulate in the ER. In this review, we examine the role of HMG-CoA reductase degradation protein 1 (HRD1) and the chaperone protein-disulfide isomerase (PDI), which are both produced in the ER in response to stress. We discuss the importance of HRD1 in degrading amyloid precursor protein (APP) and Parkin-associated endothelin receptor-like receptor (Pael-R) to protect against neuronal death. PDI and the chemical chaperone 4-phenyl-butyrate also exert neuroprotective effects. We discuss the pathophysiological roles of ER stress, UPR, and the induction and neuroprotective effects of HRD1 and PDI, which may represent significant targets for novel AD and PD therapies.
Highlights
The prevalence of dementia is estimated to be approximately 25,000,000 people worldwide and is increasing exponentially as the number of senescent individuals increase
In an attempt to isolate and identify novel human unfolded protein responses (UPR) genes, we previously focused on the ER-associated protein degradation (ERAD) genes Hrd1p/Der3p, which exhibit E3 activity and are localized in the endoplasmic reticulum (ER) of yeast
This study was limited regarding the number of number of specimens and consideration of the clinical states, these findings suggest that HMG-CoA reductase degradation protein 1 (HRD1) participates in reducing Aβ levels, thereby suppressing the pathogenesis of Alzheimer’s disease (AD)
Summary
The prevalence of dementia is estimated to be approximately 25,000,000 people worldwide and is increasing exponentially as the number of senescent individuals increase. More than half of dementia patients have Alzheimer’s disease (AD). A number of environmental, biological, chemical, and physical factors can cause pathological states. The pathogenesis of a complex combination of genetic and epigenetic factors, a common mechanism may be neuronal neurodegeneration involves a complex combination of genetic and epigenetic factors, a common death in the brain. The cerebral systems in the supply andofthe astroglial and microglial cells in and the microglial maintenance neurons, have important glucose and oxygen and the astroglial cells of in the maintenance of neurons, roles have in preventing neurodegeneration. Is a ubiquitin E3 ligase, and that of the molecular chaperone protein-disulfide isomerase (PDI) in AD in AD and PD. These proteins are all produced in the ER in response to stress.
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