New imaging technique lets researchers track effects of mutant SOD1 inside motor neurons
Mutations in the SOD1 protein have been identified in approximately 20 percent of familial ALS patients. Research done by Packard Center scientists helped identify how changes to SOD1 could lead to the motor neuron degeneration seen in ALS. Scientists now believe that one of the mechanisms whereby mutant SOD1 proteins cause motor neuron damage is by affecting the localization of mitochondria, which provides the cell with energy and regulates calcium signaling in motor neurons.
To see how dysfunction of mitochondrial dynamics led to motor neuron deterioration, Packard researchers Giovanni Manfredi and Jordi Magrané, neuroscientists at Weill Medical College of Cornell University, Serge Przedborski, a P2ALS investigator from Columbia Univeristy and their colleagues captured a series of images of live motor neurons from healthy rats and rats carrying an SOD1 mutation. Attaching a small, colored fluorescent tag to motor neuron mitochondria allowed the researchers to follow the mitochondria moving and fusing with each other over time. In healthy motor neurons, the mitochondria moved along the axon, and changed shape by fusion. In the mutant SOD1 motor neurons, however, mitochondria were much smaller, didn’t move along the axon properly, and didn’t show normal fusion with other mitochondria. These abnormalities correlated with loss of mitochondrial function and mislocalization of mitochondria relative to the neuronal synapses.
These results, published today in the Journal of Neuroscience, provide visual confirmation that mutant SOD1 could lead to mitochondrial dysfunction and motor neuron degeneration.
The imaging techniques developed by Manfredi and colleagues are useful tools to study mitochondrial dynamics in living animals as well, an approach which is currently being used to characterize mitochondrial dynamics in vivo and to see how drugs targeting the mitochondria may restore mitochondrial function in real time, work that has been supported by the Packard Center.