4.7 Article

Distal denervation in the SOD1 knockout mouse correlates with loss of mitochondria at the motor nerve terminal

Journal

EXPERIMENTAL NEUROLOGY
Volume 318, Issue -, Pages 251-257

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2019.05.008

Keywords

Superoxide dismutase-1; Oxidative stress; Axonal degeneration; Mitochondria; Neuromuscular junction; Amyotrophic lateral sclerosis

Categories

Funding

  1. Muscular Dystrophy Association
  2. NIH [1R01NS062055]
  3. AAN/ALSA Clinician Scientist Development award

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Impairment of mitochondrial transport has long been implicated in the pathogenesis of neuropathy and neurodegeneration. However, the role of mitochondria in stabilizing motor nerve terminals at neuromuscular junction (NMJ) remains unclear. We previously demonstrated that mice lacking the antioxidant enzyme, superoxide dismutase-1 (Sod1 -/-), develop progressive NMJ denervation. This was rescued by expression of SOD1 exclusively in the mitochondrial intermembrane space (MitoSOD1/Sod1 -/-), suggesting that oxidative stress within mitochondria drives denervation in these animals. However, we also observed reduced mitochondrial density in Sod1 -/- motor axons in vitro. To investigate the relationship between mitochondrial density and NMJ innervation in vivo, we crossed Sod1 -/- mice with the fluorescent reporter strains Thyl-YFP and Thyl-mitoCFP. We identified an age -dependent loss of mitochondria at motor nerve terminals in Sod1 -/- mice, that closely correlated with NMJ denervation, and was rescued by MitoSOD1 expression. To test whether augmenting mitochondrial transport rescues Sod1 -/- axons, we generated transgenic mice overexpressing the mitochondrial cargo adaptor, Mirol. This led to a partial rescue of mitochondrial density at motor nerve terminals by 12 months of age, but was insufficient to prevent denervation. These findings suggest that loss of mitochondria in the distal motor axon may contribute to denervation in Sod1 -/- mice, perhaps via loss of key mitochondrial functions such as calcium buffering and/or energy production.

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