Mutant SOD1(G93A) triggers mitochondrial fragmentation in spinal cord motor neurons: Neuroprotection by SIRT3 and PGC-1 alpha
Abbreviated Journal Title
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
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.
Neurobiology of Disease
"Mutant SOD1(G93A) triggers mitochondrial fragmentation in spinal cord motor neurons: Neuroprotection by SIRT3 and PGC-1 alpha" (2013). Faculty Bibliography 2010s. 4711.