Mutant SOD1(G93A) triggers mitochondrial fragmentation in spinal cord motor neurons: Neuroprotection by SIRT3 and PGC-1 alpha

    Authors

    W. J. Song; Y. T. Song; B. Kincaid; B. Bossy;E. Bossy-Wetzel

    Comments

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    Abbreviated Journal Title

    Neurobiol. Dis.

    Keywords

    Mitochondrial dynamics; Axonal trafficking; Dominant-negative DRP1; Real-time imaging; Astrocyte; Motor neuron; SIRT3; ALS; PGC-1 alpha; AMYOTROPHIC-LATERAL-SCLEROSIS; RECEPTOR-GAMMA COACTIVATOR-1-ALPHA; DYNAMIN-RELATED PROTEIN-1; CALORIC RESTRICTION; SUPEROXIDE-DISMUTASE; OXIDATIVE STRESS; LIFE-SPAN; WILD-TYPE; SIRT3-MEDIATED DEACETYLATION; SACCHAROMYCES-CEREVISIAE; Neurosciences

    Abstract

    Mutations in the Cu/Zn Superoxide Dismutase (SOD1) gene cause an inherited form of ALS with upper and lower motor neuron loss. The mechanism underlying mutant SOD1-mediated motor neuron degeneration remains unclear. While defects in mitochondrial dynamics contribute to neurodegeneration, including ALS, previous reports remain conflicted. Here, we report an improved technique to isolate, transfect, and culture rat spinal cord motor neurons. Using this improved system, we demonstrate that mutant SOD1(G93A) triggers a significant decrease in mitochondrial length and an accumulation of round fragmented mitochondria. The increase of fragmented mitochondria coincides with an arrest in both anterograde and retrograde axonal transport and increased cell death. In addition, mutant SOD1G93A induces a reduction in neurite length and branching that is accompanied with an abnormal accumulation of round mitochondria in growth cones. Furthermore, restoration of the mitochondrial fission and fusion balance by dominant-negative dynamin-related protein 1 (DRP1) expression rescues the mutant SOD1(G93A)-induced defects in mitochondrial morphology, dynamics, and cell viability. Interestingly, both SIRT3 and PGC-1 alpha protect against mitochondrial fragmentation and neuronal cell death by mutant SOD1(G93A). This data suggests that impairment in mitochondrial dynamics participates in ALS and restoring this defect might provide protection against mutant SOD1G93A-induced neuronal injury. Published by Elsevier Inc.

    Journal Title

    Neurobiology of Disease

    Volume

    51

    Publication Date

    1-1-2013

    Document Type

    Article

    Language

    English

    First Page

    72

    Last Page

    81

    WOS Identifier

    WOS:000314627100009

    ISSN

    0969-9961

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