title: Proteolipid protein-deficient myelin promotes axonal mitochondrial dysfunction via altered metabolic coupling.
abstract: Hereditary spastic paraplegia (HSP) is a neurological syndrome characterized by degeneration of central nervous system (CNS) axons. Mutated HSP proteins include myelin proteolipid protein (PLP) and axon-enriched proteins involved in mitochondrial function, smooth endoplasmic reticulum (SER) structure, and microtubule (MT) stability/function. We characterized axonal mitochondria, SER, and MTs in rodent optic nerves where PLP is replaced by the peripheral nerve myelin protein, P0(P0-CNS mice). Mitochondrial pathology and degeneration were prominent in juxtaparanodal axoplasm at 1 mo of age. In wild-type (WT) optic nerve axons, 25% of mitochondria-SER associations occurred on extensions of the mitochondrial outer membrane. Mitochondria-SER associations were reduced by 86% in 1-mo-old P0-CNS juxtaparanodal axoplasm. 1-mo-old P0-CNS optic nerves were more sensitive to oxygen-glucose deprivation and contained less adenosine triphosphate (ATP) than WT nerves. MT pathology and paranodal axonal ovoids were prominent at 6 mo. These data support juxtaparanodal mitochondrial degeneration, reduced mitochondria-SER associations, and reduced ATP production as causes of axonal ovoid formation and axonal degeneration.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Grahame J
authors.identifier: http://orcid.org/0000-0003-3956-2206
authors.initials: GJ
authors.lastname: Kidd
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Nobuhiko
authors.identifier: http://orcid.org/0000-0002-6536-2753
authors.initials: N
authors.lastname: Ohno
authors.affiliation: National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Guy A
authors.identifier: http://orcid.org/0000-0002-1878-8735
authors.initials: GA
authors.lastname: Perkins
authors.affiliation: National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA 92093.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Chinthasagar
authors.identifier: http://orcid.org/0000-0001-5759-5496
authors.initials: C
authors.lastname: Bastian
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Sylvain
authors.identifier: http://orcid.org/0000-0002-7506-9585
authors.initials: S
authors.lastname: Brunet
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Selva
authors.identifier: http://orcid.org/0000-0003-1123-3582
authors.initials: S
authors.lastname: Baltan
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195 trappb@ccf.org.
authors.forename: Bruce D
authors.identifier: http://orcid.org/0000-0001-6682-3737
authors.initials: BD
authors.lastname: Trapp
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D001692:Biological Transport; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004734:Energy Metabolism; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D051336:Mitochondrial Membranes / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000172:deficiency* / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D009900:Optic Nerve; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism
chemical_list: D018991:Myelin Proteolipid Protein; D016875:tau Proteins; D000255:Adenosine Triphosphate