Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD remains incompletely understood. Environmental factors, oxidative damage, misfolded protein aggregates, ubiquitin-proteasome system impairment, and mitochondrial dysfunction might all be involved. Recent studies point to activation of endoplasmic reticulum (ER) stress-mediated cell death linked to PD. Accumulation of unfolded and/or misfolded proteins in the ER lumen induces ER stress. To withstand such potentially lethal conditions, intracellular signaling pathways collectively termed the unfolded protein responses (UPR) are activated. The UPR include translational attenuation, induction of ER resident chaperones, and degradation of misfolded proteins through the ER-associated degradation. In case of severe and/or prolonged ER stress, cellular signals leading to cell death are activated. Accumulating evidence suggests that ER stress induced by aberrant protein degradation is implicated in PD. Here the authors review the emerging role of ER stress in PD and related disorders, and highlight current knowledge in this field that may reveal novel insight into disease mechanisms and help to provide novel avenues to potential therapies.
"Stress signals culminate in overloading ER with proteins and exhausting the ER machinery. ER stress is thought to be and in certain cases proved to play a key role in diseases like Alzheimer’s disease (Salminen et al., 2009; Viana et al., 2012), Parkinson’s disease (Wang and Takahashi, 2007; Cali et al., 2011), amyotrophic lateral sclerosis (ALS) (Lautenschlaeger et al., 2012; Tadic et al., 2014), poly glutamine diseases (Vidal et al., 2011), ischemia (Doroudgar et al., 2009), atherosclerosis (Zhou and Tabas, 2013), bipolar disorder (Hayashi et al., 2009), prion diseases (Xu and Zhu, 2012), cancer (Tsai and Weissman, 2010), diabetes (Papa, 2012), auto immune disorders (Zhong et al., 2012), and cardiovascular disorders (Minamino et al., 2010). Interestingly, there are reports demonstrating that ER stress inhibition could protect against neuronal injury (Qi et al., 2004; Sokka et al., 2007), ischemia (Nakka et al., 2010), cardiovascular diseases (Teng et al., 2011), respiratory disorders (Hoffman et al., 2013), atherosclerosis (Zhou et al., 2013), and sleep apnea (Zhu et al., 2008), in in vivo murine models. "
[Show abstract][Hide abstract] ABSTRACT: Execution of fundamental cellular functions demands regulated protein folding homeostasis. Endoplasmic reticulum (ER) is an active organelle existing to implement this function by folding and modifying secretory and membrane proteins. Loss of protein folding homeostasis is central to various diseases and budding evidences suggest ER stress as being a major contributor in the development or pathology of a diseased state besides other cellular stresses. The trigger for diseases may be diverse but, inflammation and/or ER stress may be basic mechanisms increasing the severity or complicating the condition of the disease. Chronic ER stress and activation of the unfolded-protein response (UPR) through endogenous or exogenous insults may result in impaired calcium and redox homeostasis, oxidative stress via protein overload thereby also influencing vital mitochondrial functions. Calcium released from the ER augments the production of mitochondrial Reactive Oxygen Species (ROS). Toxic accumulation of ROS within ER and mitochondria disturbs fundamental organelle functions. Sustained ER stress is known to potentially elicit inflammatory responses via UPR pathways. Additionally, ROS generated through inflammation or mitochondrial dysfunction could accelerate ER malfunction. Dysfunctional UPR pathways have been associated with a wide range of diseases including several neurodegenerative diseases, stroke, metabolic disorders, cancer, inflammatory disease, diabetes mellitus, cardiovascular disease, and others. In this review, we have discussed the UPR signaling pathways, and networking between ER stress-induced inflammatory pathways, oxidative stress, and mitochondrial signaling events, which further induce or exacerbate ER stress.
"When the synthesis of secretory proteins increases and overwhelms the capacity of ER chaperones and the ERAD, unfolded proteins accumulate in the ER and form aggregates (ER stress), which are highly toxic to cells and induce apoptosis . Neurons are especially sensitive to ER stress, and ER stress can cause various neurodegenerative diseases, including Alzheimer's disease , Parkinson's disease  and prion disease . ER stress also involved in the onset of other diseases such as diabetes mellitus [7–9], atherosclerosis , and UVA-induced cell damage . "
[Show abstract][Hide abstract] ABSTRACT: The endoplasmic reticulum (ER) stress response is a cytoprotective mechanism that maintains homeostasis of the ER by upregulating the capacity of the ER in accordance with cellular demands. If the ER stress response cannot function correctly, because of reasons such as aging, genetic mutation or environmental stress, unfolded proteins accumulate in the ER and cause ER stress-induced apoptosis, resulting in the onset of folding diseases, including Alzheimer's disease and diabetes mellitus. Although the mechanism of the ER stress response has been analyzed extensively by biochemists, cell biologists and molecular biologists, many aspects remain to be elucidated. For example, it is unclear how sensor molecules detect ER stress, or how cells choose the two opposite cell fates (survival or apoptosis) during the ER stress response. To resolve these critical issues, structural and computational approaches will be indispensable, although the mechanism of the ER stress response is complicated and difficult to understand holistically at a glance. Here, we provide a concise introduction to the mammalian ER stress response for structural and computational biologists.
Computational and Structural Biotechnology Journal 03/2013; 6(7):e201303010. DOI:10.5936/csbj.201303010
"Here, we show for the first time that inflammatory signaling through TNF and ceramide induces ER stress in DA neuron-like cells and that SMase inhibition attenuates ER stress and prevents TNF-induced cytotoxicity (as measured independently by MTS and LDH release assays). ATF6 is a direct target of the ER stress response  and is known to activate transcription of chaperone proteins  to facilitate protein folding and processing capacity; ATF6 also activates ER-associated degradation (ERAD) to promote the degradation of terminally misfolded proteins . Mechanistically, defective calcium homeostasis, especially increased intracellular Ca2+ release, presumably from the ER, has been implicated in neuronal cell death in mouse models exhibiting increased CNS glucosylsphingosine levels which can also suppress neuronal outgrowth [49,64,65]. "
[Show abstract][Hide abstract] ABSTRACT: Dopaminergic (DA) neurons in the ventral midbrain selectively degenerate in Parkinson's disease (PD) in part because their oxidative environment in the substantia nigra (SN) may render them vulnerable to neuroinflammatory stimuli. Chronic inhibition of soluble Tumor Necrosis Factor (TNF) with dominant-negative TNF inhibitors protects DA neurons in rat models of parkinsonism, yet the molecular mechanisms and pathway(s) that mediate TNF toxicity remain(s) to be clearly identified. Here we investigated the contribution of ceramide sphingolipid signaling in TNF-dependent toxicity.
Ceramide dose-dependently reduced the viability of DA neuroblastoma cells and primary DA neurons and pharmacological inhibition of sphingomyelinases (SMases) with three different inhibitors during TNF treatment afforded significant neuroprotection by attenuating increased endoplasmic reticulum (ER) stress, loss of mitochondrial membrane potential, caspase-3 activation and decreases in Akt phosphorylation. Using lipidomics mass spectrometry we confirmed that TNF treatment not only promotes generation of ceramide, but also leads to accumulation of several atypical deoxy-sphingoid bases (DSBs). Exposure of DA neuroblastoma cells to atypical DSBs in the micromolar range reduced cell viability and inhibited neurite outgrowth and branching in primary DA neurons, suggesting that TNF-induced de novo synthesis of atypical DSBs may be a secondary mechanism involved in mediating its neurotoxicity in DA neurons.
We conclude that TNF/TNFR1-dependent activation of SMases generates ceramide and sphingolipid species that promote degeneration and caspase-dependent cell death of DA neurons. Ceramide and atypical DSBs may represent novel drug targets for development of neuroprotective strategies that can delay or attenuate the progressive loss of nigral DA neurons in patients with PD.
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