Esclerosis Lateral

Modulation of Astrocytic Mitochondrial Function by Dichloroacetate Improves Survival and Motor Performance in Inherited Amyotrophic Lateral Sclerosis
´ ´ Ernesto Miquel1., Adriana Cassina2,3., Laura Martınez-Palma1, Carmen Bolatto1, Emiliano Trıas4, 1 2,3 5,3 1,3 Mandi Gandelman , Rafael Radi , Luis Barbeito , Patricia Cassina *
´ ´ ´ ´ 1 Departamento de Histologıa y Embriologıa, Facultad deMedicina, Universidad de la Republica, Montevideo, Uruguay, 2 Departamento de Bioquımica, Facultad de ´ ´ Medicina, Universidad de la Republica, Montevideo, Uruguay, 3 CEINBIO, Facultad de Medicina, Universidad de la Republica, Montevideo, Uruguay, 4 Instituto de ´ Investigaciones Biologicas Clemente Estable, Montevideo, Uruguay, 5 Institut Pasteur de Montevideo, Montevideo, Uruguay

AbstractMitochondrial dysfunction is one of the pathogenic mechanisms that lead to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). Astrocytes expressing the ALS-linked SOD1G93A mutation display a decreased mitochondrial respiratory capacity associated to phenotypic changes that cause them to induce motor neuron death. Astrocyte-mediated toxicity can be prevented by mitochondria-targetedantioxidants, indicating a critical role of mitochondria in the neurotoxic phenotype. However, it is presently unknown whether drugs currently used to stimulate mitochondrial metabolism can also modulate ALS progression. Here, we tested the disease-modifying effect of dichloroacetate (DCA), an orphan drug that improves the functional status of mitochondria through the stimulation of the pyruvatedehydrogenase complex activity (PDH). Applied to astrocyte cultures isolated from rats expressing the SOD1G93A mutation, DCA reduced phosphorylation of PDH and improved mitochondrial coupling as expressed by the respiratory control ratio (RCR). Notably, DCA completely prevented the toxicity of SOD1G93A astrocytes to motor neurons in coculture conditions. Chronic administration of DCA (500 mg/L) in thedrinking water of mice expressing the SOD1G93A mutation increased survival by 2 weeks compared to untreated mice. Systemic DCA also normalized the reduced RCR value measured in lumbar spinal cord tissue of diseased SOD1G93A mice. A remarkable effect of DCA was the improvement of grip strength performance at the end stage of the disease, which correlated with a recovery of the neuromuscular junction areain extensor digitorum longus muscles. Systemic DCA also decreased astrocyte reactivity and prevented motor neuron loss in SOD1G93A mice. Taken together, our results indicate that improvement of the mitochondrial redox status by DCA leads to a disease-modifying effect, further supporting the therapeutic potential of mitochondria-targeted drugs in ALS.
´ ´ Citation: Miquel E, Cassina A,Martınez-Palma L, Bolatto C, Trıas E, et al. (2012) Modulation of Astrocytic Mitochondrial Function by Dichloroacetate Improves Survival and Motor Performance in Inherited Amyotrophic Lateral Sclerosis. PLoS ONE 7(4): e34776. doi:10.1371/journal.pone.0034776 Editor: Sergio T. Ferreira, Federal University of Rio de Janeiro, Brazil Received December 22, 2011; Accepted March 5, 2012; Published April 3, 2012Copyright: ß 2012 Miquel et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ´ Funding: This work was supported by grants from Amyotrophic Lateral Sclerosis Association (ALSA, www.alsa.org), Grant #1734 to PC;Comision Sectorial de ´ ´ ´ ´ ´ Investigacion Cientıfica-Universidad de la Republica, Uruguay (CSIC, www.csic.edu.uy) and Agencia Nacional de Investigacion e Innovacion, Uruguay (ANII, www. ´sicas, Uruguay (PEDECIBA, www.pedeciba.edu.uy). EM is recipient of a fellowship from ANII. anii.org.uy) to RR and Programa para el Desarrollo de las Ciencias Ba The funders had no role in study design, data...