Entanglement of UPRER in Aging Driven Neurodegenerative Diseases

Abstract

The endoplasmic reticulum (ER) is an indispensable cellular organelle that remains highly active in neuronal cells. The ER bears the load of maintaining protein homeostasis in the cellular network by managing the folding of incoming nascent peptides; however, the stress imposed by physiological/environmental factors can cause ER dysfunctions that lead to the activation of ER unfolded protein response (UPRER). Aging leads to deterioration of several cellular pathways and therefore weakening of the UPRER. The decline in functioning of the UPRER during aging results in accumulation of misfolded proteins that becomes intracellular inclusions in neuronal cells, resulting in toxicity manifested as neurodegenerative diseases. With ascension in cases of neurodegenerative diseases, understanding the enigma behind aging driven UPRER dysfunction may lead to possible treatments.

HMG-CoA Reductase Inhibitors Relieve Endoplasmic Reticulum Stress by Autophagy Inhibition in Rats With Permanent Brain Ischemia

“…To further discuss autophagy-induced apoptosis, we found in the PMCAO groups that autophagosomes were triggered by ER swelling in the ischemic area, and in turn, autophagy also affects ER stress. Cross talking with UPR/ER effector molecules, LC3 canonically triggers the degradation of organelles/molecules in the cytosol and potentiates the adaptive ability of the cell by clearing the load of misfolded proteins from the ER lumen ( Rahman et al, 2017 ) to affect apoptosis ( Talma et al, 2016 ). ER stress is initiated through the IRE-1, PERK, and ATF6 pathways in mammalian cells ( Nakka et al, 2016 ; Rahman et al, 2017 ).…”

“…Cross talking with UPR/ER effector molecules, LC3 canonically triggers the degradation of organelles/molecules in the cytosol and potentiates the adaptive ability of the cell by clearing the load of misfolded proteins from the ER lumen ( Rahman et al, 2017 ) to affect apoptosis ( Talma et al, 2016 ). ER stress is initiated through the IRE-1, PERK, and ATF6 pathways in mammalian cells ( Nakka et al, 2016 ; Rahman et al, 2017 ). IRE1α from the ER might be involved in integrating ERS signaling with inflammatory-response signaling for activating both JNK and NF-κB ( Wu et al, 2014 ) to trigger cell apoptosis.…”

Dissecting Endoplasmic Reticulum Unfolded Protein Response (UPRER) in Managing Clandestine Modus Operandi of Alzheimer’s Disease

“…The UPR ER embodies a complex network comprised of three stress-responsive transmembrane proteins, Protein Kinase RNA like ER kinase (PERK), Inositol Requiring Element 1 (IRE1) and Activating Transcription Factor 6 (ATF6; Figure 1 ; Schroder and Kaufman, 2005 ; Walter and Ron, 2011 ; Minakshi et al, 2017 ; Rahman et al, 2017 ). PERK, a type 1 transmembrane kinase protein, gets trans-autophosphorylated and homodimerized after activation, thereby promoting phosphorylation of serine residues on cytoplasmic eIF2α (eukaryotic initiation factor 2 alpha; Harding et al, 1999 ; Bertolotti et al, 2000 ; Ma et al, 2002 ; Marciniak et al, 2006 ).…”

Expedition into Taurine Biology: Structural Insights and Therapeutic Perspective of Taurine in Neurodegenerative Diseases

“…The lack, on the therapeutic front, of treatments for slowing the rate of occurrence of NDs, these often become devastating, not only for the patients and their families (for care and dependency), but often also leaving a deep scar in terms of the mounting economic burden. With huge socioeconomic constraints, the etiology of NDs [Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and others] has become a burning issue that needs properly addressing, not only in terms of understanding the disease mechanism, but also in terms of the advancement of developing potential treatment regimes that can control the progression of the NDs [2][3][4][5][6][7].…”