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endoplasmic reticulum and A53T and parkinson

Mei Liu, Lixia Qin, Lili Wang, Jieqiong Tan, Hainan Zhang, Jianguang Tang, Xiangmin Shen, Liming Tan, Chunyu Wang
Although previous work has demonstrated that the overexpression of wild‑type or mutant α‑synuclein (α‑syn) can induce cell death via a number of different mechanisms, including oxidative stress, dysfunction of the ubiquitin‑proteasome degradation system, mitochondrial damage and endoplasmic reticulum (ER) stress, research interest has primarily focused on neurons. However, there is accumulating evidence that suggests that astrocytes may be involved in the earliest changes, as well as the progression of Parkinson's disease (PD), though the role of α‑syn in astrocytes has not been widely studied...
May 9, 2018: Molecular Medicine Reports
Emanuela Colla, Giulia Panattoni, Alessio Ricci, Caterina Rizzi, Lucia Rota, Nicola Carucci, Verdiana Valvano, Francesco Gobbo, Simona Capsoni, Michael K Lee, Antonino Cattaneo
α-synuclein (αS) is a small protein that self-aggregates into α-helical oligomer species and subsequently into larger insoluble amyloid fibrils that accumulate in intraneuronal inclusions during the development of Parkinson's disease. Toxicity of αS oligomers and fibrils has been long debated and more recent data are suggesting that both species can induce neurodegeneration. However while most of these data are based on differences in structure between oligomer and aggregates, often preassembled in vitro, the in vivo situation might be more complex and subcellular locations where αS species accumulate, rather than their conformation, might contribute to enhanced toxicity...
March 2018: Neurobiology of Disease
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: Recently, the incidence of Parkinson's disease has shown a tendency to move to a younger population, linked to the constantly increasing stressors of modern society. However, this relationship remains obscure. Here, we have investigated the contribution of stress and the mechanisms underlying this change. EXPERIMENTAL APPROACH: Ten-month-old α-synuclein A53T mice, a model of Parkinson's disease (PD), were treated with chronic restraint stress (CRS) to simulate a PD-sensitive person with constant stress stimulation...
February 2018: British Journal of Pharmacology
Hyo-Jin Park, Daniel Ryu, Mayur Parmar, Benoit I Giasson, Nikolaus R McFarland
Abnormal accumulation of α-synuclein (αSyn) has been linked to endoplasmic-reticulum (ER) stress, defective intracellular protein/vesicle trafficking, and cytotoxicity. Targeting factors involved in ER-related protein processing and trafficking may, therefore, be a key to modulating αSyn levels and associated toxicity. Recently retention in endoplasmic reticulum 1 (RER1) has been identified as an important ER retrieval/retention factor for Alzheimer's disease proteins and negatively regulates amyloid-β peptide levels...
2017: PloS One
Sylvia Torres-Odio, Jana Key, Hans-Hermann Hoepken, Júlia Canet-Pons, Lucie Valek, Bastian Roller, Michael Walter, Blas Morales-Gordo, David Meierhofer, Patrick N Harter, Michel Mittelbronn, Irmgard Tegeder, Suzana Gispert, Georg Auburger
BACKGROUND: PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson's disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types. METHODS: Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms...
August 2, 2017: Journal of Neuroinflammation
Martial Kamdem Mbefo, Mohamed-Bilal Fares, Katerina Paleologou, Abid Oueslati, Guowei Yin, Sandra Tenreiro, Madalena Pinto, Tiago Outeiro, Markus Zweckstetter, Eliezer Masliah, Hilal A Lashuel
Although α-synuclein (α-syn) phosphorylation has been considered as a hallmark of sporadic and familial Parkinson disease (PD), little is known about the effect of PD-linked mutations on α-syn phosphorylation. In this study, we investigated the effects of the A30P, E46K, and A53T PD-linked mutations on α-syn phosphorylation at residues Ser-87 and Ser-129. Although the A30P and A53T mutants slightly affected Ser(P)-129 levels compared with WT α-syn, the E46K mutation significantly enhanced Ser-129 phosphorylation in yeast and mammalian cell lines...
April 10, 2015: Journal of Biological Chemistry
Emanuela Colla, Philippe Coune, Ying Liu, Olga Pletnikova, Juan C Troncoso, Takeshi Iwatsubo, Bernard L Schneider, Michael K Lee
Accumulation of misfolded α-synuclein (αS) is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other α-synucleinopathies. However, how αS causes neurodegeneration is unresolved. Because cellular accumulation of misfolded proteins can lead to endoplasmic reticulum stress/unfolded protein response (ERS/UPR), chronic ERS could contribute to neurodegeneration in α-synucleinopathy. Using the A53T mutant human αS transgenic (A53TαS Tg) mouse model of α-synucleinopathy, we show that disease onset in the αS Tg model is coincident with induction of ER chaperones in neurons exhibiting αS pathology...
March 7, 2012: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Cherine Belal, Neema J Ameli, Adam El Kommos, Spencer Bezalel, Aziz M Al'Khafaji, Mohamed R Mughal, Mark P Mattson, George A Kyriazis, Björn Tyrberg, Sic L Chan
Endoplasmic reticulum (ER) stress has been implicated as an initiator or contributing factor in neurodegenerative diseases. The mechanisms that lead to ER stress and whereby ER stress contributes to the degenerative cascades remain unclear but their understanding is critical to devising effective therapies. Here we show that knockdown of Herp (Homocysteine-inducible ER stress protein), an ER stress-inducible protein with an ubiquitin-like (UBL) domain, aggravates ER stress-mediated cell death induced by mutant α-synuclein (αSyn) that causes an inherited form of Parkinson's disease (PD)...
March 1, 2012: Human Molecular Genetics
P Wang, B Li, L Zhou, E Fei, G Wang
Endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases, and the KDEL (Lys-Asp-Glu-Leu motif) receptor (KDELR) plays a key role in ER quality control and in the ER stress response. The subcellular distribution of KDELR is dynamic and related to its ligand binding status and its expression level. Here, we show that KDELR mRNA is upregulated upon thapsigargin treatment, which induces ER stress. Moreover, overexpressed KDELR partially redistributes to the lysosome and activates autophagy. The R169N mutant, a ligand binding-defective form of KDELR, and D193N, a transport-defective form of KDELR, both fail to trigger autophagy...
September 8, 2011: Neuroscience
Yong Joo Lee, Shaoxiao Wang, Sunny R Slone, Talene A Yacoubian, Stephan N Witt
We identified three S. cerevisiae lipid elongase null mutants (elo1Δ, elo2Δ, and elo3Δ) that enhance the toxicity of alpha-synuclein (α-syn). These elongases function in the endoplasmic reticulum (ER) to catalyze the elongation of medium chain fatty acids to very long chain fatty acids, which is a component of sphingolipids. Without α-syn expression, the various elo mutants showed no growth defects, no reactive oxygen species (ROS) accumulation, and a modest decrease in survival of aged cells compared to wild-type cells...
2011: PloS One
Nandhakumar Thayanidhi, Jared R Helm, Deborah C Nycz, Marvin Bentley, Yingjian Liang, Jesse C Hay
Toxicity of human alpha-synuclein when expressed in simple organisms can be suppressed by overexpression of endoplasmic reticulum (ER)-to-Golgi transport machinery, suggesting that inhibition of constitutive secretion represents a fundamental cause of the toxicity. Whether similar inhibition in mammals represents a cause of familial Parkinson's disease has not been established. We tested elements of this hypothesis by expressing human alpha-synuclein in mammalian kidney and neuroendocrine cells and assessing ER-to-Golgi transport...
June 1, 2010: Molecular Biology of the Cell
Zhiyin Xun, Renã A Sowell, Thomas C Kaufman, David E Clemmer
A global isotopic labeling strategy combined with multidimensional liquid chromatographies and tandem mass spectrometry was used for quantitative proteome analysis of a presymptomatic A53T alpha-synuclein Drosophila model of Parkinson disease (PD). Multiple internal standard proteins at different concentration ratios were spiked into samples from PD-like and control animals to assess quantification accuracy. Two biological replicates isotopically labeled in forward and reverse directions were analyzed. A total of 253 proteins were quantified with a minimum of two identified peptide sequences (for each protein); 180 ( approximately 71%) proteins were detected in both forward and reverse labeling measurements...
July 2008: Molecular & Cellular Proteomics: MCP
Wanli W Smith, Haibing Jiang, Zhong Pei, Yuji Tanaka, Hokuto Morita, Akira Sawa, Valina L Dawson, Ted M Dawson, Christopher A Ross
Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein is a major component of Lewy bodies in sporadic PD, and mutations in alpha-synuclein cause autosomal-dominant hereditary PD. Here, we generated A53T mutant alpha-synuclein-inducible PC12 cell lines using the Tet-off regulatory system. Inducing expression of A53T alpha-synuclein in differentiated PC12 cells decreased proteasome activity, increased the intracellular ROS level and caused up to approximately 40% cell death, which was accompanied by mitochondrial cytochrome C release and elevation of caspase-9 and -3 activities...
December 15, 2005: Human Molecular Genetics
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