Mitochondrial Modulation by Dichloroacetate Reduces Toxicity of Aberrant Glial Cells and Gliosis in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis.

Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics
Laura Martínez-PalmaPatricia Cassina

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron (MN) degeneration and gliosis. Neonatal astrocytes obtained from the SOD1G93A rat model of ALS exhibit mitochondrial dysfunction and neurotoxicity that can be reduced by dichloroacetate (DCA), a metabolic modulator that has been used in humans, and shows beneficial effects on disease outcome in SOD1G93A mice. Aberrant glial cells (AbGC) isolated from the spinal cords of adult paralytic SOD1G93A rats exhibit highly proliferative and neurotoxic properties and may contribute to disease progression. Here we analyze the mitochondrial activity of AbGC and whether metabolic modulation would modify their phenotypic profile. Our studies revealed fragmented mitochondria and lower respiratory control ratio in AbGC compared to neonatal SOD1G93A and nontransgenic rat astrocytes. DCA (5 mM) exposure improved AbGC mitochondrial function, reduced their proliferative rate, and importantly, decreased their toxicity to MNs. Furthermore, oral DCA administration (100 mg/kg, 10 days) to symptomatic SOD1G93A rats reduced MN degeneration, gliosis, and the number of GFAP/S100β double-labeled hypertrophic glial cells in the spinal cord. DCA treatment o...Continue Reading

References

Dec 26, 2001·Journal of Neuroscience Research·Patricia CassinaLuis Barbeito
Jan 31, 2002·Proceedings of the National Academy of Sciences of the United States of America·David S HowlandJeffrey D Rothstein
Oct 4, 2006·Neuron·Séverine BoilléeDon W Cleveland
Apr 17, 2007·Nature Neuroscience·Makiko NagaiSerge Przedborski
Apr 3, 2008·Glia·Mathilde GavilletPierre J Magistretti
Apr 18, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Patricia CassinaRafael Radi
Aug 15, 2009·Journal of Neuropathology and Experimental Neurology·Nigel A CalcuttPeter W Stacpoole
May 14, 2010·Science Translational Medicine·E D MichelakisK C Petruk
Jun 10, 2010·International Journal of Cancer. Journal International Du Cancer·Luke H StockwinDianne L Newton
Nov 3, 2010·Lancet Neurology·Luc DupuisJean-Philippe Loeffler
Jul 6, 2011·The Biochemical Journal·Martin D Brand, David G Nicholls
Aug 13, 2011·Nature Biotechnology·Amanda M Haidet-PhillipsBrian K Kaspar
Oct 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Pablo Díaz-AmarillaLuis Barbeito
Oct 4, 2012·Free Radical Biology & Medicine·Chad A GallowayYisang Yoon
Apr 25, 2013·Molecular Genetics and Metabolism·Monica AbdelmalakPeter W Stacpoole
Oct 27, 2014·Apoptosis : an International Journal on Programmed Cell Death·L M DelaneyB L Coomber
Jan 9, 2015·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Kristopher G HootenStanley H Appel
Mar 25, 2015·British Journal of Pharmacology·Ruben OrihuelaGaylia Jean Harry
Jul 15, 2015·Cell Metabolism·Peter H G M WillemsWerner J H Koopman
Oct 9, 2015·Biology of Reproduction·Adriana Maria CassinaRossana Sapiro
May 5, 2016·Pharmacogenomics·Margaret O James, Peter W Stacpoole
Oct 30, 2016·Pharmacology & Therapeutics·Margaret O JamesPeter W Stacpoole
Feb 9, 2017·Annals of Clinical and Translational Neurology·Ashley E FrakesBrian K Kaspar
Mar 2, 2017·Scientific Reports·Gabriel N ValbuenaHector C Keun
Jul 4, 2017·Neuroscience Letters·Emma F SmithKurt J De Vos
Jul 6, 2017·Biochemical and Biophysical Research Communications·David F Kashatus
Jul 13, 2017·The New England Journal of Medicine·Robert H Brown, Ammar Al-Chalabi
Sep 20, 2017·Trends in Immunology·Angelika S Rambold, Erika L Pearce
Nov 28, 2017·Frontiers in Immunology·Stephanie A AmiciMireia Guerau-de-Arellano
Dec 7, 2017·Liver International : Official Journal of the International Association for the Study of the Liver·Xiacheng SunJinliang Xing
Feb 25, 2018·Glia·L Felipe BarrosRaymond A Swanson
Apr 12, 2018·Genetic Testing and Molecular Biomarkers·Taimour LangaeePeter W Stacpoole

❮ Previous
Next ❯

Methods Mentioned

BETA
transgenic
confocal microscopy
transmission electron microscopy
genotyping

Software Mentioned

Fiji
DataLab
GraphPad Prism
Adobe Photoshop

Related Concepts

Related Feeds

ALS: Phenotypes

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized phenotypically by progressive muscle weakness. Clinical phenotypes of ALS can be classified based on the pattern, level, and area of onset (e.g. bulbar, cervical, lumbar). Here is the latest research investigating phenotypes of ALS.

Astrocytes & Neurodegeneration

Astrocytes are important for the health and function of the central nervous system. When these cells stop functioning properly, either through gain of function or loss of homeostatic controls, neurodegenerative diseases can occur. Here is the latest research on astrocytes and neurodegeneration.

ALS: Pathogenic Mechanisms

Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disorder characterized by muscle weakness. Here is the latest research investigating pathogenic mechanisms that underlie this genetically heterogeneous disorder.

Amyloid Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive nervous system disease associated with the death of neurons that control voluntary muscles. Discover the latest research on ALS here.

Astrocytes

Astrocytes are glial cells that support the blood-brain barrier, facilitate neurotransmission, provide nutrients to neurons, and help repair damaged nervous tissues. Here is the latest research.