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parkinson's disease and endoplasmic reticulum stress

Paola Imbriani, Tommaso Schirinzi, Maria Meringolo, Nicola B Mercuri, Antonio Pisani
Significant advances have been made in the understanding of the numerous mechanisms involved in Parkinson's disease (PD) pathogenesis. The identification of PD pathogenic mutations and the use of different animal models have contributed to better elucidate the processes underlying the disease. Here, we report a brief survey of some relevant cellular mechanisms, including autophagic-lysosomal dysfunction, endoplasmic reticulum stress, and mitochondrial impairment, with the main aim to focus on their potential convergent roles in determining early alterations at the synaptic level, mainly consisting in a decrease in dopamine release at nigrostriatal terminals and loss of synaptic plasticity at corticostriatal synapses...
2018: Frontiers in Neurology
Mona Dehhaghi, Fatemeh Mohammadipanah, Gilles J Guillemin
Age-related disorders impose noticeable financial and emotional burdens on society. This impact is becoming more prevalent with the increasing incidence of neurodegenerative diseases and is causing critical concerns for treatment of patients worldwide. Parkinson's disease, Alzheimer's disease, multiple sclerosis and motor neuron disease are the most prevalent and the most expensive to treat neurodegenerative diseases globally. Therefore, exploring effective therapies to overcome these disorders is a necessity...
February 27, 2018: Neurotoxicology
Patricia Gómez-Suaga, José M Bravo-San Pedro, Rosa A González-Polo, José M Fuentes, Mireia Niso-Santano
Mitochondria form close physical contacts with a specialized domain of the endoplasmic reticulum (ER), known as the mitochondria-associated membrane (MAM). This association constitutes a key signaling hub to regulate several fundamental cellular processes. Alterations in ER-mitochondria signaling have pleiotropic effects on a variety of intracellular events resulting in mitochondrial damage, Ca2+ dyshomeostasis, ER stress and defects in lipid metabolism and autophagy. Intriguingly, many of these cellular processes are perturbed in neurodegenerative diseases...
March 1, 2018: Cell Death & Disease
Priyanka Dutta, Leila Dargahi, Kara E O'Connell, Ashini Bolia, Banu Ozkan, Andreas W Sailer, Kumlesh K Dev
Parkin associated endothelin like receptor (PAELR) is G-protein coupled and ubiquitinated by parkin, promoting its degradation. In autosomal recessive Parkinson's disease, mutations in parkin lead to PAELR aggregation in the endoplasmic reticulum (ER), ER stress, neurotoxicity and cell death. We have identified previously that the protein kinase C interacting protein (PICK1) interacts with and regulates the expression and cell toxicity of PAELR. Here, we experimentally identify and provide in-silico modelling of a novel interaction between PAELR and GABARAPL2 (γ-aminobutyrate type A receptor associated protein like 2), which is an autophagosome-specific Ub-like protein implicated in vesicle trafficking and autophagy...
February 26, 2018: Neuroscience Letters
Diego Grassi, Shannon Howard, Minghai Zhou, Natalia Diaz-Perez, Nicolai T Urban, Debbie Guerrero-Given, Naomi Kamasawa, Laura A Volpicelli-Daley, Philip LoGrasso, Corinne Ida Lasmézas
Exposure of cultured primary neurons to preformed α-synuclein fibrils (PFFs) leads to the recruitment of endogenous α-synuclein and its templated conversion into fibrillar phosphorylated α-synuclein (pα-synF) aggregates resembling those involved in Parkinson's disease (PD) pathogenesis. Pα-synF was described previously as inclusions morphologically similar to Lewy bodies and Lewy neurites in PD patients. We discovered the existence of a conformationally distinct, nonfibrillar, phosphorylated α-syn species that we named "pα-syn*...
February 27, 2018: Proceedings of the National Academy of Sciences of the United States of America
Jacopo J V Branca, Gabriele Morucci, Mario Maresca, Barbara Tenci, Roberta Cascella, Ferdinando Paternostro, Carla Ghelardini, Massimo Gulisano, Lorenzo Di Cesare Mannelli, Alessandra Pacini
Cadmium (Cd), a worldwide occupational pollutant, is an extremely toxic heavy metal, capable of damaging several organs, including the brain. Its toxicity has been related to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The neurotoxic potential of Cd has been attributed to the changes induced in the brain enzyme network involved in counteracting oxidative stress. On the other hand, it is also known that trace elements, such as zinc (Zn) and selenium (Se), required for optimal brain functions, appears to have beneficial effects on the prevention of Cd intoxication...
January 29, 2018: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Roberta Balestrino, Anthony H V Schapira
Parkinson disease (PD) is a complex neurodegenerative disease characterised by multiple motor and non-motor symptoms. In the last 20 years, more than 20 genes have been identified as causes of parkinsonism. Following the observation of higher risk of PD in patients affected by Gaucher disease, a lysosomal disorder caused by mutations in the glucocerebrosidase (GBA) gene, it was discovered that mutations in this gene constitute the single largest risk factor for development of idiopathic PD. Patients with PD and GBA mutations are clinically indistinguishable from patients with idiopathic PD, although some characteristics emerge depending on the specific mutation, such as slightly earlier onset...
February 1, 2018: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
Gabriela Mercado, Valentina Castillo, Paulina Soto, Nélida López, Jeffrey M Axten, Pablo Sardi, Jeroen J M Hoozemans, Claudio Hetz
Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to the progressive decline of motor control due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Accumulating evidence suggest that altered proteostasis is a salient feature of PD, highlighting perturbations to the endoplasmic reticulum (ER), the main compartment involved in protein folding and secretion. PERK is a central ER stress sensor that enforces adaptive programs to recover homeostasis through a block of protein translation and the induction of the transcription factor ATF4...
January 17, 2018: Neurobiology of Disease
D Lin, Y Liang, D Zheng, Y Chen, X Jing, M Lei, Z Zeng, T Zhou, X Wu, S Peng, K Huang, L Yang, S Xiao, J Liu, E Tao
In order to uncover the remarkable pathogenic genes or molecular pathological process in Parkinson's disease (PD), we employed a microarray analysis upon the cellular PD model induced by rotenone. Compared to the control group, 2174 genes were screened out to be expressed differently in the rotenone-induced group by certain criterion. GO analysis and the pathways analysis showed the significant enrichment of genes that were associated with the biological process of cell cycle, apoptotic process, organelle fusion, mitochondrial lesion, endoplasmic reticulum stress and so on...
January 10, 2018: Gene
Kunikazu Tanji, Fumiaki Mori, Yasuo Miki, Jun Utsumi, Hidenao Sasaki, Akiyoshi Kakita, Hitoshi Takahashi, Koichi Wakabayashi
Ubiquitination, a fundamental post-translational modification of intracellular proteins, is enzymatically reversed by deubiquitinase enzymes (deubiquitinases). >90 deubiquitinases have been identified. One of these enzymes, YOD1, possesses deubiquitinase activity and is similar to ovarian tumor domain-containing protein 1, which is associated with regulation of the endoplasmic reticulum (ER)-associated degradation pathway. Indeed, YOD1 is reported to be involved in the ER stress response induced by mislocalization of unfolded proteins in mammalian cells...
April 2018: Neurobiology of Disease
Yasmeen M Taalab, Nour Ibrahim, Ahmed Maher, Mubashir Hassan, Wael Mohamed, Ahmed A Moustafa, Mohamed Salama, Dina Johar, Larry Bernstein
Neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease, prion disease, and amyotrophic lateral sclerosis, are a dissimilar group of disorders that share a hallmark feature of accumulation of abnormal intraneuronal or extraneuronal misfolded/unfolded protein and are classified as protein misfolding disorders. Cellular and endoplasmic reticulum (ER) stress activates multiple signaling cascades of the unfolded protein response (UPR). Consequently, translational and transcriptional alterations in target gene expression occur in response directed toward restoring the ER capacity of proteostasis and reestablishing the cellular homeostasis...
January 5, 2018: Reviews in the Neurosciences
Mark Harmon, Philip Larkman, Giles Hardingham, Mandy Jackson, Paul Skehel
Close contacts between the endoplasmic reticulum membrane and the mitochondrial outer membrane facilitate efficient transfer of lipids between the organelles and coordinate Ca2+ signalling and stress responses. Changes to this coupling is associated with a number of metabolic disorders and neurodegenerative diseases including Alzheimer's, Parkinson's and motor neuron disease. The distance between the two membranes at regions of close apposition is below the resolution of conventional light microscopy, which makes analysis of these interactions challenging...
December 12, 2017: Scientific Reports
Kenta Arai, Haruhito Ueno, Yuki Asano, Gaurango Chakrabarty, Shingo Shimodaira, Govindasamy Mugesh, Michio Iwaoka
The protein disulfide isomerase (PDI) family, found in the endoplasmic reticulum (ER) of the eukaryotic cell, catalyzes the formation and cleavage of disulfide bonds and thereby helps in protein folding. A decrease in PDI activity under ER stress conditions leads to protein misfolding, which is responsible for the progression of various human diseases, such as Alzheimer's, Parkinson's, diabetes mellitus, and atherosclerosis. Here we report that water-soluble cyclic diselenides mimic the multifunctional activity of the PDI family by facilitating oxidative folding, disulfide formation/reduction, and repair of the scrambled disulfide bonds in misfolded proteins...
February 2, 2018: Chembiochem: a European Journal of Chemical Biology
Upasana Ganguly, Sankha Shubhra Chakrabarti, Upinder Kaur, Anwesha Mukherjee, Sasanka Chakrabarti
There is a growing body of evidence in animal and cell based models of Parkinson's disease (PD) to suggest that overexpression and / or abnormal accumulation and aggregation of α-synuclein can trigger neuronal death. This important role of α-synuclein in PD pathogenesis is supported by the fact that duplication, triplication and mutations of α-synuclein gene cause familial forms of PD. The overexpression and accumulation of α-synuclein within neurons may involve both transcriptional and post-transcriptional mechanisms including a decreased degradation of the protein through proteasomal or autophagic processes...
November 28, 2017: Current Neuropharmacology
Lesly Puspita, Sun Young Chung, Jae-Won Shim
Parkinson's disease (PD) is a chronic and progressive neurodegeneration of dopamine neurons in the substantia nigra. The reason for the death of these neurons is unclear; however, studies have demonstrated the potential involvement of mitochondria, endoplasmic reticulum, α-synuclein or dopamine levels in contributing to cellular oxidative stress as well as PD symptoms. Even though those papers had separately described the individual roles of each element leading to neurodegeneration, recent publications suggest that neurodegeneration is the product of various cellular interactions...
November 28, 2017: Molecular Brain
Yi-Wei Wang, Qin Zhou, Xiang Zhang, Qing-Qing Qian, Jia-Wen Xu, Peng-Fei Ni, Yan-Ning Qian
BACKGROUND: Neuroinflammation, which ultimately leads to neuronal loss, is considered to play a crucial role in numerous neurodegenerative diseases. The neuroinflammatory process is characterized by the activation of glial cells such as microglia. Endoplasmic reticulum (ER) stress is commonly associated with impairments in neuronal function and cognition, but its relationship and role in neurodegeneration is still controversial. Recently, it was confirmed that nonharmful levels of ER stress protected against experimental Parkinson's disease...
November 28, 2017: Journal of Neuroinflammation
Wenming Li, Jinqiu Zhu, Juan Dou, Hua She, Kai Tao, Haidong Xu, Qian Yang, Zixu Mao
Endoplasmic reticulum (ER) and lysosomes coordinate a network of key cellular processes including unfolded protein response (UPR) and autophagy in response to stress. How ER stress is signaled to lysosomes remains elusive. Here we find that ER disturbance activates chaperone-mediated autophagy (CMA). ER stressors lead to a PERK-dependent activation and recruitment of MKK4 to lysosomes, activating p38 MAPK at lysosomes. Lysosomal p38 MAPK directly phosphorylates the CMA receptor LAMP2A at T211 and T213, which causes its membrane accumulation and active conformational change, activating CMA...
November 24, 2017: Nature Communications
Peizhou Jiang, Dennis W Dickson
Parkinson's disease (PD) is a chronic, progressive movement disorder of adults and the second most common neurodegenerative disease after Alzheimer's disease. Neuropathologic diagnosis of PD requires moderate-to-marked neuronal loss in the ventrolateral substantia nigra pars compacta and α-synuclein (αS) Lewy body pathology. Nigrostriatal dopaminergic neurodegeneration correlates with the Parkinsonian motor features, but involvement of other peripheral and central nervous system regions leads to a wide range of non-motor features...
January 2018: Acta Neuropathologica
Zhao Zhang, Shi-Feng Chu, Sha-Sha Wang, Yi-Na Jiang, Yan Gao, Peng-Fei Yang, Qi-Di Ai, Nai-Hong Chen
BACKGROUND AND PURPOSE: The incidence of Parkinson's disease exhibited a younger tendency in recent years with the constantly increased stressors of modern society, but this relationship remains obscured. We performed this study to investigate whether stress contributes to this tendency and identify the executor during this process. EXPERIMENTAL APPROACH: Ten-month-old α-synuclein A53T mice, a PD mice model, were treated with chronic restraint stress (CRS) to simulate a PD-sensitive person with constant stress stimulation...
November 11, 2017: British Journal of Pharmacology
Jinar Rostami, Staffan Holmqvist, Veronica Lindström, Jessica Sigvardson, Gunilla T Westermark, Martin Ingelsson, Joakim Bergström, Laurent Roybon, Anna Erlandsson
Many lines of evidence suggest that the Parkinson's disease (PD)-related protein α-synuclein (α-SYN) can propagate from cell to cell in a prion-like manner. However, the cellular mechanisms behind the spreading remain elusive. Here, we show that human astrocytes derived from embryonic stem cells actively transfer aggregated α-SYN to nearby astrocytes via direct contact and tunneling nanotubes (TNTs). Failure in the astrocytes' lysosomal digestion of excess α-SYN oligomers results in α-SYN deposits in the trans-Golgi network followed by endoplasmic reticulum swelling and mitochondrial disturbances...
December 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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