O1‐04‐06: Zinc and oxidative stress induces depletion and aggregation of endogenous TDP‐43статья из журнала
Аннотация: Ubiquitinated neuronal aggregates containing TDP-43 are pathological hallmarks in the spectrum of frontotemporal lobar dementia and amyotrophic lateral sclerosis. Changes to TDP-43 metabolism have also been reported in Alzheimer's disease brain tissue. In affected neurons, the TDP-43 undergoes C-terminal fragmentation, phosphorylation and ubiquitination and forms aggregates in the cytoplasm or nucleus. While in vitro studies have been able to re-capitulate these features using transfected cell culture models, little is known about the biochemical mechanisms that underlie pathological changes to endogenous TDP-43. As altered metal ion homeostasis and increased oxidative stress are central features of neurodegeneration, including FTD and ALS, we sought to determine the effects of these factors on endogenous TDP-43 metabolism in mammalian cells. Cultures of neuronal-like SY5Y cells were treated with biometals or subjected to oxidative insult and changes to endogenous TDP-43 metabolism examined by immunoblot and immunofluorescence. Treatment of SY5Y cells expressing endogenous TDP-43 with zinc (Zn) induced depletion of TDP-43 expression and formation of inclusions in the nucleus and cytoplasm that were TDP-43 positive. No evidence of C-terminal fragmentation, phosphorylation or ubiquitination was observed. The depletion and aggregation of TDP-43 was associated with the specific action of Zn and was not seen with copper or iron. Inclusions of TDP-43 were inhibited by treatment of cells with a cell permeable free radical scavenger (MnTMPyP) while exposure of cells to the superoxide generator, paraquat, induced similar formation of inclusions. These findings suggest that increased metal-associated oxidative stress, which is a common feature of neurodegeneration, may enhance aggregation of endogenous neuronal TDP-43. Our studies describe for the first time specific induction of endogenous TDP-43 aggregation in neuronal-like cells and suggest that specific Zn and oxidative stress-associated processes could affect TDP-43 metabolism in neurodegenerative diseases.
Год издания: 2010
Авторы: Anthony R. White, Aphrodite Caragounis, Jodi Meyerowitz, Katherine A. Price, Cynthia P.W. Soon, Gulay Filiz, Colin L. Masters, Qiao‐Xin Li, Peter J. Crouch
Издательство: Wiley
Источник: Alzheimer s & Dementia
Ключевые слова: Amyotrophic Lateral Sclerosis Research, Alzheimer's disease research and treatments, Cholinesterase and Neurodegenerative Diseases
Открытый доступ: bronze
Том: 6
Выпуск: 4S_Part_3