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Characterization of the Mitochondrial Aerobic Metabolism in the Pre- and Perisynaptic Districts of the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disease characterized by muscle wasting, weakness, and spasticity due to a progressive degeneration of cortical, brainstem, and spinal motor neurons. The etiopathological causes are still largely obscure, although astrocytes definitely play a role in neuronal damage. Several mechanisms have been proposed to concur to neurodegeneration in ALS, including mitochondrial dysfunction. We have previously shown profound modifications of glutamate release and presynaptic plasticity in the spinal cord of the SOD1G93A mouse model of ALS. In this work, we characterized, for the first time, the aerobic metabolism in two specific compartments actively involved in neurotransmission (i.e. the presynaptic district, using purified synaptosomes, and the perisynaptic astrocyte processes, using purified gliosomes) in SOD1G93A mice at different stages of the disease. ATP/AMP ratio was lower in synaptosomes isolated from the spinal cord, but not from other brain areas, of SOD1G93A vs. control mice. The energy impairment was linked to altered oxidative phosphorylation (OxPhos) and increment of lipid peroxidation. These metabolic dysfunctions were present during disease progression, starting at the very pre-symptomatic stages, and did not depend on a different number of mitochondria or a different expression of OxPhos proteins. Conversely, gliosomes showed a reduction of the ATP/AMP ratio only at the late stages of the disease and an increment of oxidative stress also in the absence of a significant decrement in OxPhos activity. Data suggest that the presynaptic neuronal moiety plays a pivotal role for synaptic energy metabolism dysfunctions in ALS. Changes in the perisynaptic compartment seem subordinated to neuronal damage.

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Acknowledgements

The authors are indebted to Mr. Giuseppe Marazzotta for his help in maintaining the SOD1G93Aand the wtSOD1 mouse colonies. The authors gratefully acknowledge the undergraduate students Cesare Cecchini, Mirna Nitro, and Roncallo Roberta, for their helpful technical support.

Funding

This work was supported by research grants from the Italian Ministry of University (PRIN Project No. 2016058401 to GB and SIR Project No. RBSI14B1Z to M.M.) and from the Motor Neuron Disease Association (Project No. April16/848-791) to GB.

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  1. Silvia Ravera, Tiziana Bonifacino, Isabella Panfoli and Giambattista Bonanno contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Unit of Pharmacology and Toxicology, University of Genoa, 16148, Genoa, Italy

    Silvia Ravera, Tiziana Bonifacino, Marco Milanese, Elena Gallia, Francesca Provenzano & Giambattista Bonanno

  2. Department of Pharmacy, Laboratory of Biochemistry, University of Genoa, 16132, Genoa, Italy

    Martina Bartolucci & Isabella Panfoli

  3. Center of Excellence for Biomedical Research, University of Genoa, 16132, Genoa, Italy

    Marco Milanese & Giambattista Bonanno

  4. Department of Experimental Medicine, Human Anatomy, University of Genoa, 16132, Genoa, Italy

    Katia Cortese

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  1. Silvia Ravera
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Correspondence to Giambattista Bonanno.

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Ravera, S., Bonifacino, T., Bartolucci, M. et al. Characterization of the Mitochondrial Aerobic Metabolism in the Pre- and Perisynaptic Districts of the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis. Mol Neurobiol 55, 9220–9233 (2018). https://doi.org/10.1007/s12035-018-1059-z

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  • DOI: https://doi.org/10.1007/s12035-018-1059-z

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