Distinct multilevel misregulations of Parkin and PINK1 revealed in cell and animal models of TDP-43 proteinopathy

Cell Death & Disease
Xing SunYanshan Fang

Abstract

Parkin and PINK1 play an important role in mitochondrial quality control, whose malfunction may also be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Excessive TDP-43 accumulation is a pathological hallmark of ALS and is associated with Parkin protein reduction in spinal cord neurons from sporadic ALS patients. In this study, we reveal that Parkin and PINK1 are differentially misregulated in TDP-43 proteinopathy at RNA and protein levels. Using knock-in flies, mouse primary neurons, and TDP-43Q331K transgenic mice, we further unveil that TDP-43 downregulates Parkin mRNA, which involves an unidentified, intron-independent mechanism and requires the RNA-binding and the protein-protein interaction functions of TDP-43. Unlike Parkin, TDP-43 does not regulate PINK1 at an RNA level. Instead, excess of TDP-43 causes cytosolic accumulation of cleaved PINK1 due to impaired proteasomal activity, leading to compromised mitochondrial functions. Consistent with the alterations at the molecular and cellular levels, we show that transgenic upregulation of Parkin but downregulation of PINK1 suppresses TDP-43-induced degenerative phenotypes in a Drosophila model of ALS. Together, these findings highlight the challenge ass...Continue Reading

References

Oct 25, 2001·Proceedings of the National Academy of Sciences of the United States of America·T OsterwalderH Keshishian
Mar 19, 2003·Proceedings of the National Academy of Sciences of the United States of America·Jessica C GreeneLeo J Pallanck
Apr 13, 2005·Proceedings of the National Academy of Sciences of the United States of America·Alexandra BeilinaMark R Cookson
Jul 9, 2005·Proceedings of the National Academy of Sciences of the United States of America·Guang-Ho ChaKyoung Sang Cho
Oct 7, 2005·Human Molecular Genetics·Laura SilvestriGiorgio Casari
Jan 31, 2008·Proceedings of the National Academy of Sciences of the United States of America·Angela C PooleLeo J Pallanck
Nov 26, 2008·The Journal of Cell Biology·Derek NarendraRichard J Youle
Jan 14, 2009·Acta Neuropathologica·Tetsuaki AraiHaruhiko Akiyama
Feb 4, 2010·PLoS Biology·Derek P NarendraRichard J Youle
Mar 18, 2010·Nature Reviews. Neurology·Alice S Chen-PlotkinJohn Q Trojanowski
Apr 20, 2010·Human Molecular Genetics·Clotilde Lagier-TourenneDon W Cleveland
Aug 13, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ya-Fei XuLeonard Petrucelli
Dec 9, 2010·Human Molecular Genetics·Emma DeasNicholas W Wood
Feb 8, 2011·Lancet·Matthew C KiernanMargaret C Zoing
Mar 2, 2011·Nature Neuroscience·James R TollerveyJernej Ule
Mar 2, 2011·Nature Neuroscience·Magdalini PolymenidouDon W Cleveland
Mar 23, 2011·Molecular and Cellular Neurosciences·Shangxi XiaoJanice Robertson
Dec 1, 2011·Nature Reviews. Neuroscience·Edward B LeeJohn Q Trojanowski
Jun 19, 2012·Molecular and Cellular Neurosciences·Mauro CozzolinoMaria Teresa Carrì
Oct 2, 2012·Nature Neuroscience·Clotilde Lagier-TourenneGene W Yeo
Feb 6, 2013·Proceedings of the National Academy of Sciences of the United States of America·Eveline S ArnoldDon W Cleveland
May 8, 2013·Proceedings of the National Academy of Sciences of the United States of America·Anil RanaDavid W Walker
Jul 6, 2013·Cell Reports·Andrew R BassettJi-Long Liu
Jul 31, 2013·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Yasuko Toyoshima, Hitoshi Takahashi
Aug 13, 2013·Neuron·Shuo-Chien LingDon W Cleveland
Oct 15, 2013·Autophagy·Koji Yamano, Richard J Youle
Oct 24, 2013·British Journal of Pharmacology·H Muyderman, T Chen
Dec 5, 2013·Journal of Neurochemistry·Michaeline HebronCharbel E-H Moussa
Apr 23, 2014·The Journal of Cell Biology·Lesley A KaneRichard J Youle
May 3, 2014·Nature·Fumika KoyanoNoriyuki Matsuda
May 23, 2014·Human Molecular Genetics·Chen WenqiangCharbel E-H Moussa
Sep 10, 2014·Advances in Experimental Medicine and Biology·Stefanie GerstbergerThomas Tuschl
Jan 23, 2015·Neuron·Alicia M Pickrell, Richard J Youle
May 20, 2015·The Journal of Biological Chemistry·Grace G Y LimKah-Leong Lim

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Citations

Jun 26, 2020·Frontiers in Cell and Developmental Biology·Stylianos Ravanidis, Epaminondas Doxakis
Nov 11, 2020·Acta Neuropathologica Communications·Peter M J QuinnC Henrique Alves
Jan 9, 2021·Cell Death and Differentiation·Marlene F SchmidtGrant Dewson
Apr 10, 2021·Trends in Neurosciences·Joseph R KlimKevin Eggan
May 1, 2021·International Journal of Molecular Sciences·Francesco LiguoriCinzia Volonté
May 6, 2021·International Journal of Molecular Sciences·Alistair WoodSarah Lyn Rea
Mar 28, 2021·Nature Communications·Minwoo BaekNam Chul Kim
Jun 1, 2021·Frontiers in Molecular Neuroscience·Katarzyna Gaweda-WalerychCezary Zekanowski
Jul 30, 2021·Cellular and Molecular Life Sciences : CMLS·Francesco LiguoriCinzia Volonté
Aug 8, 2021·International Journal of Molecular Sciences·Fiona BrightYazi D Ke
Nov 3, 2021·The Journal of Cell Biology·Xue DengYanshan Fang
Aug 25, 2019·Molecular and Cellular Neurosciences·Ju GaoXinglong Wang

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Methods Mentioned

BETA
transgenic
RNA-seq
reverse transcription-PCR
PCR
cleavage assay
transfection
transgenics
electrophoresis
confocal microscopy
Assay

Software Mentioned

Adobe Photoshop
ImageQuant TL
ImageJ

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