The Common Cellular Events in the Neurodegenerative Diseases and the Associated Role of Endoplasmic Reticulum Stress

Abstract

Neurodegenerative diseases are inseparably linked with aging and increase as life expectancy extends. There are common dysfunctions in various cellular events shared among neurogenerative diseases, such as calcium dyshomeostasis, neuroinflammation, and age-associated decline in the autophagy-lysosome system. However, most of all, the prominent pathological feature of neurodegenerative diseases is the toxic buildup of misfolded protein aggregates and inclusion bodies accompanied by an impairment in proteostasis. Recent studies have suggested a close association between endoplasmic reticulum (ER) stress and neurodegenerative pathology in cellular and animal models as well as in human patients. The contribution of mutant or misfolded protein-triggered ER stress and its associated signaling events, such as unfolded protein response (UPR), to the pathophysiology of various neurodegenerative disorders, including Alzheimer's, Parkinson's, and Huntington's disease, amyotrophic lateral sclerosis, and prion disease, is described here. Impaired UPR action is commonly attributed to exacerbated ER stress, pathogenic protein aggregate accumulation, and deteriorating neurodegenerative pathologies. Thus, activating certain UPR components has been shown to alleviate ER stress and its associated neurodegeneration. However, uncontrolled activation of some UPR factors has also been demonstrated to worsen neurodegenerative phenotypes, suggesting that detailed molecular mechanisms around ER stress and its related neurodegenerations should be understood to develop effective therapeutics against aging-associated neurological syndromes. We also discuss current therapeutic endeavors, such as the development of small molecules that selectively target individual UPR components and address ER stress in general.

Keywords: Alzheimer’s disease; ER stress; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; endoplasmic reticulum; misfolded protein; neurodegenerative disease; prion disease; unfolded protein response.

Figure 1

Summary of UPR signaling cascade. UPR is initiated by GRP78’s dissociation from UPR components on the ER membrane under ER stress. PERK and IRE1 undergo autotransphosphorylation after their dimerization or oligomerization, and ATF6 is translocated to Golgi and cleaved by protease S1P and S2P. UPR activation enhances target gene expression to restore ER protein folding capacity or triggers cell death. TXNIP induced by PERK and IRE1 also activates the inflammasome and triggers subsequent cell death.

Figure 2

Misfolded protein clearance by autophagy and ERAD. For ERAD, unfolded/misfolded proteins are retrotranslocated to the cytosol through retrotranslocons such as Derlin and Hrd1, and ubiquitinated by E3 ligase (e.g., Hrd1; Sel1 is a cofactor of Hrd1). Polyubiquitinated ERAD substrate proteins are recognized and degraded by 26S proteasome in the cytosol. Protein aggregates, macromolecules, and organelles are also cleared via the autophagy-lysosomal pathway.

Figure 3

ER stress and neurodegeneration triggered by misfolded protein aggregates. Genetic mutations, aging, environmental insults, and various cellular stresses disrupt ER protein quality control and proper folding of proteins. Increased protein misfolding induces ER stress and accelerates the accumulation of disease-associated protein aggregates. ER chaperone activities and UPR pathways are enhanced as adaptive stress responses to alleviate ER stress. As a result, various chaperones and protein clearance mechanisms such as autophagy and ERAD contribute to refolding or eliminating misfolded proteins. However, when sustained ER stress in the neuron exceeds the capacity of adaptive responses to cope with protein misfolding, ER stress can lead to neuronal cell death and neuroinflammation, contributing to the development of neurodegenerative pathologies.