Activation of the Unfolded Protein Response Is an Early Event in Alzheimer’s and Parkinson’s Disease

Abstract

Background: Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by the accumulation and aggregation of misfolded proteins. Disturbed homeostasis in the endoplasmic reticulum leads to accumulation of misfolded proteins, which triggers a stress response called the unfolded protein response (UPR) that protects the cell against the toxic buildup of misfolded proteins. Objective: In this paper, we will briefly review the early involvement of the UPR in the pathology of AD and PD. Methods: Expression of UPR activation markers was analyzed in human brain tissue using immunohistochemistry and Western blot analysis. Results: Neuropathological studies demonstrate that UPR activation markers are increased in neurons in AD and PD. In AD, UPR activation markers are observed in neurons with diffuse staining of phosphorylated tau protein. In PD, increased immunoreactivity for UPR activation markers is detected in neuromelanin containing dopaminergic neurons of the substantia nigra, which colocalize with diffuse α-synuclein staining. Conclusion: UPR activation is closely associated with the first stages of accumulation and aggregation of the toxic proteins involved in AD and PD. Studies of postmortem brain tissue indicate that UPR activation is an early event in neurodegeneration.

Programmed Cell Death in Parkinson's Disease

“…Dysfunctional UPS and protein misfolding are some of the key pathological features of PD and activation of UPR seems to be an early event in PD (Hoozemans et al 2012). Parkin mutations are associated with ER stress-induced cell death, while overexpressing wild-type Parkin was protective (Imai et al 2000;Dawson and Dawson 2003).…”

Xenobiotic Perturbation of ER Stress and the Unfolded Protein Response

“…Marketed pharmaceuticals developed for various diseases can also cause ER stress by either on-or off-target mechanisms for which they were developed including bortezomib, nelfinavir, atazanavir, ritonavir, lopinavir, sorafenib, indomethacin, and celecoxib. Katayama et al 1999;Niwa et al 1999;Milhavet et al 2002;Unterberger et al 2006;Hoozemans et al 2012 Parkinson Shuda et al 2003;Fujimoto et al 2003;Fernandez et al 2000;Jamora, Dennert, and Lee 1996 An example of on-target ER stress modulation is seen with bortezomib (Velcade) developed as a proteasome inhibitor that induces ER stress in several cell types, particularly multiple myeloma cells which contribute to its anticancer cytotoxic activity Frankland-Searby and Bhaumik 2012;Obeng et al 2006). These malignant cells derived from plasma cells secrete extensive amounts of immunoglobulins and are thus particularly vulnerable to disruptions in ER homeostasis.…”

Bajijiasu Ameliorates β-Amyloid-Triggered Endoplasmic Reticulum Stress and Related Pathologies in an Alzheimer’s Disease Model

“…When proteins become misfolded in the ER, the UPR is elicited to maintain homeostasis [29, 30]. ER stress and activated UPR signaling are detected in the brains of both AD patients and AD animal models [31, 32]. AD is a very complex disease caused by a complicated interaction among genetic and environmental factors [33].…”