Background. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective and progressive loss of motorneurons. Several etiologic factors are involved in ALS pathogenesis, however it is well accepted that a severe mitochondrial dysfunction leads to an unavoidable neuronal death. Despite this, there is no certainty on the intimate mechanisms sustaining the progressive neuronal demise. Therefore, the aim of this study is to decipher the processes and the molecular mechanisms that contribute to mitochondrial stress linked to ALS-related neurodegeneration. Methods. We chose as representative ALS biological model SOD1-G93A transgenic mice at different developmental/disease stages. Proteomics analysis of mitochondrial enriched fractions derived from spinal cord tissues was carried out to evaluate the adaptation of ALS mitochondrial proteome. Differential protein expression was evaluated by shotgun proteomics analysis based on nLC-HDMSe. Moreover, a targeted proteomics analysis of key ALS proteins has been performed in mitochondria derived from motor cortex, brainstem and cerebellum tissues, focusing on persulfide containing proteins and peptides. Results. Proteomic analysis revealed interesting mitochondrial proteins differentially expressed in SOD1-G93A mice spinal cord compared to wt. Among these, subunits of cytochrome complexes, heat shock proteins (e.g. HSP10, 60 and 70), protein disulfide isomerase, GAPDH. Their expression has been also studied in mitochondria derived from other neuronal tissues. Conclusion. Adaptation of ALS mitochondria proteome repertoire has revealed an impairment of mitochondrial quality control, system addressed to maintain mitochondrial homeostasis of via their regulated biogenesis and protein degradation. Moreover, most of differentially expressed proteins show a common element, they have persulfide sites and are H₂S targets. Therefore, we retain that hydrogen sulphide (H₂S) further distress and amplify an already compromised mitochondrial function in the vulnerable ALS motor neurons.
Impairment of Protein Mitochondrial Quality Control (PMQC) in Amyotrophic Lateral Sclerosis / V. Greco, A. Spalloni, G. Mazzuccato, L. Pieroni, V. Corasolla Carregari, M. Ronci, A. Soggiu, C. Piras, P. Roncada, P. Longone, A. Urbani. ((Intervento presentato al 16. convegno Human Proteome Organization World Congress tenutosi a Dublin nel 2017.
Impairment of Protein Mitochondrial Quality Control (PMQC) in Amyotrophic Lateral Sclerosis
A. Soggiu;C. Piras;
2017
Abstract
Background. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective and progressive loss of motorneurons. Several etiologic factors are involved in ALS pathogenesis, however it is well accepted that a severe mitochondrial dysfunction leads to an unavoidable neuronal death. Despite this, there is no certainty on the intimate mechanisms sustaining the progressive neuronal demise. Therefore, the aim of this study is to decipher the processes and the molecular mechanisms that contribute to mitochondrial stress linked to ALS-related neurodegeneration. Methods. We chose as representative ALS biological model SOD1-G93A transgenic mice at different developmental/disease stages. Proteomics analysis of mitochondrial enriched fractions derived from spinal cord tissues was carried out to evaluate the adaptation of ALS mitochondrial proteome. Differential protein expression was evaluated by shotgun proteomics analysis based on nLC-HDMSe. Moreover, a targeted proteomics analysis of key ALS proteins has been performed in mitochondria derived from motor cortex, brainstem and cerebellum tissues, focusing on persulfide containing proteins and peptides. Results. Proteomic analysis revealed interesting mitochondrial proteins differentially expressed in SOD1-G93A mice spinal cord compared to wt. Among these, subunits of cytochrome complexes, heat shock proteins (e.g. HSP10, 60 and 70), protein disulfide isomerase, GAPDH. Their expression has been also studied in mitochondria derived from other neuronal tissues. Conclusion. Adaptation of ALS mitochondria proteome repertoire has revealed an impairment of mitochondrial quality control, system addressed to maintain mitochondrial homeostasis of via their regulated biogenesis and protein degradation. Moreover, most of differentially expressed proteins show a common element, they have persulfide sites and are H₂S targets. Therefore, we retain that hydrogen sulphide (H₂S) further distress and amplify an already compromised mitochondrial function in the vulnerable ALS motor neurons.
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