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.

A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development

“…However, data awareness in terms of pharmacological HD drug targets and potential agents is also crucial for novel drug discovery, design, and development. In fact, the target landscape with respect to HD is rich and diverse, which leaves much space for rational drug design approaches [ 2 , 14 , 15 , 17 , 20 , 21 , 22 , 27 , 35 , 79 ]. Many compounds with affinities to one or several of these targets have also been identified.…”

“…(v) Novel, diverse targets reducing muHTT production, enhancing muHTT degradation, and generally lowering muHTT-conferred (long-term) toxicity, and thus, positively affect HD onset and progression. These targets include CASPs [ 2 , 14 , 15 , 17 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 79 ], HSPs [ 2 , 22 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ], HDACs [ 2 , 14 , 15 , 17 , 20 , 79 , 105 ], PDEs [ 14 , 15 , 17 , 31 , 35 , 36 ], and σRs [ 14 , 15 , 35 , 37 , 79 ], but also the adenosine 2A receptor (A2AR) [ 14 , 36 ], the AMP-activated protein kinase (AMPK) [ 20 , 31 , 79 ], the ERG-associated protein with SET domain (ESET) [ 106 , 107 , 108 ], the Kelch-like ECH-associated protein (KEAP) [ 31 , 56 , 109 ,…”

“…However, no causative, disease-modifying treatment is to this date available to stop, slow down, or reverse the disease progression or even delay HD onset [ 6 ]. Several promising target structures apart from HTT have been identified to potentially be involved in the HD pathogenesis, including cysteine aspartases (caspases, CASPs) [ 2 , 14 , 15 , 17 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ], heat shock proteins (HSPs) [ 2 , 22 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ], histone deacetylases (HDACs) [ 2 , 14 , 15 , 17 , 20 ], phosphodiesterases (PDEs) [ 14 , 15 , 17 , 31 , 35 , 36 ], or sigma-receptors (σRs) [ 14 , 15 , 35 , 37 ], amongst several others. Many interesting drug candidates were discovered targeting these and other cerebral targets, however, the reason for their positive effect on in vitro or in vivo HD models remains unclear, and the mechanisms of action toward their primary targets still need to be elucidated [ 38 , 39 ].…”

Sec61 complex/translocon: The role of an atypical ER Ca2+-leak channel in health and disease

“…Obvious possible candidates include neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and Creutzfeld-Jacob disease. The role of intracellular Ca 2+ in general and of ER Ca 2+ in particular (Ureshino et al, 2019;da Costa et al, 2020;Lim et al, 2021;Callens et al, 2021;Kovacs et al, 2021;Guan et al, 2021;Huang et al, 2022;Ge et al, 2022;Kim et al, 2022) as well as of ER stress and accumulation of misfolded proteins (da Costa et al, 2020;Guan et al, 2021;Kim et al, 2022;Ren et al, 2021;Yasmeen et al, 2022;Shacham et al, 2019;Chakraborty et al, 2005) have indeed already been demonstrated in several neurodegenerative diseases.…”

Neuroprotective Effects of Neuropeptide Y on Human Neuroblastoma SH-SY5Y Cells in Glutamate Excitotoxicity and ER Stress Conditions

“…ER stress triggers an adaptive signalling reaction known as the unfolded protein response (UPR) and promotes quality control mechanisms [ 3 ]. The UPR is mediated via the activation of PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α), and activating transcription factor 6 (ATF6) pathways [ 10 ]. However, dysfunctioning and prolonged activation of UPR play an essential role in promoting pro-apoptotic events [ 11 , 12 ].…”