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endoplasmic reticulum and A53T and parkinson

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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