Abstract
Neurodegenerative diseases are characterized by progressive cognitive decline and the loss of neurons in the central nervous system; many are also characterized by abnormal aggregation of misfolded proteins. Ubiquitin (Ub) is a eukaryotic protein that plays pivotal roles in protein degradation and cellular signaling. Ubiquitinated aggregates are observed in neurodegenerative diseases; this ultimately results in reduced levels of available or free Ub. However, it remains unclear whether neurotoxicity arises from the aggregates or a deficiency of free Ub. To investigate this, we treated primary neurons of mouse embryonic brains with amyloid beta (Aβ) 42 and found that free Ub levels were decreased and cell viability was reduced in Aβ42-treated neurons. As reduced levels of free Ub are closely related to impaired function of the proteasome, we evaluated proteasome activity and found that proteasome activity was reduced upon treatment of primary neurons and mouse brain slices with Aβ42. Therefore, we conclude that proteotoxic stress from Aβ42 treatment reduced the levels of available Ub and decreased proteasome activity, resulting in inflammatory stress and apoptosis of neurons.
References
Oct 6, 1998·Annual Review of Biochemistry·A Hershko, A Ciechanover
Apr 14, 1999·Cell Death and Differentiation·A G Porter, R U Jänicke
Jun 15, 2000·Journal of Neurochemistry·J N KellerW R Markesbery
Apr 22, 2003·Annual Review of Neuroscience·Byron Caughey, Peter T Lansbury
Oct 15, 2003·Neuron·Aaron Ciechanover, Patrik Brundin
Dec 4, 2003·Molecular and Cellular Biology·John HannaDaniel Finley
Sep 30, 2005·Journal of Neurochemistry·Christopher AndersonScott M Wilson
Dec 12, 2007·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Koichi OkamotoYukio Fujita
Oct 23, 2010·Methods in Molecular Biology·W Blaine StineMary Jo LaDu
Feb 11, 2012·Neurology·J-M LeeUNKNOWN COHORT study of the HSG
Feb 23, 2013·Proceedings of the National Academy of Sciences of the United States of America·Fangfang BiHongxia Zhou
Jun 14, 2014·BMB Reports·Chul-Woo Park, Kwon-Yul Ryu
Jul 6, 2014·Brain Pathology·Kay SeidelUdo Rüb
Sep 18, 2014·CNS & Neurological Disorders Drug Targets·Ghulam M AshrafMohammad A Kamal
May 13, 2017·Annual Review of Biochemistry·Tycho E T Mevissen, David Komander
Citations
Nov 17, 2020·Frontiers in Cell and Developmental Biology·Karolina PierzynowskaGrzegorz Węgrzyn
Jan 30, 2021·Neural Regeneration Research·Chul-Woo Park, Kwon-Yul Ryu
Mar 7, 2021·Chemistry and Physics of Lipids·Sara García-ViñualesDanilo Milardi