ALS Alert Newsletter | August

Of Mutants and Mitochondria

Study adds new strength to idea of mitochondria as a keystone of ALS damage.

In the motor neurons of a healthy mouse, the GFP-tagged mitochondria (yellow-green) are distributed evenly.

Look under the microscope at the motor neurons of an ALS mouse, one that models patients with the most common familial form of the disease. Now look inside the neurons at the mitochondria, the energy centers of the cell. They look like tiny, perfect spheres. And in the motor neurons’ elongated axons, you’ll find the mitochondria clustered on one side.

Interesting, perhaps, but something here has definitely gone wrong.

Researchers have long known about a link between abnormal mitochondria and ALS, which was first discovered in the mid-1980s. And Packard investigators have continued to show differences in the way the mitochondria — also called the cell’s powerhouses — both look and behave in animal models of the disease.

But scientists have had difficulty figuring out exactly what happens in the mitochondria of animals or humans that carry the mutant SOD1 gene, and showing how this is tied to ALS symptoms.

New Results

Christine Vande Velde

A new study in mouse models, however, goes far to lift confusion. Research by Christine Vande Velde, a neuroscientist at the Université de Montréal, and a team that includes Packard investigators and advisors, clearly confirms that the misfolded protein product of the mutant SOD1 gene surfaces in the mitochondria of motor neurons.

The new work also confirms mitochondrial damage, documenting exactly how the abnormal organelles look and behave in the mutant SOD1 mice. The study, published last month in the online journal PLoS ONE, also suggests how these malfunctions might lead to the dramatic changes in neurons seen in ALS.

“This study shows that misfolded SOD1 is associated with mitochondria in motor neurons,” Vande Velde said. “This association also seems to correlate well with mitochondrial pathology” in motor neurons in mice. The clustering of the mitochondria appears to interfere with normal motor neuron functioning, which can ultimately cause those neurons to die.

What They Did

To show the precise links between mutant SOD1, mitochondrial changes and neuron damage, Vande Velde and colleagues replaced the normal SOD1 gene in laboratory mice with a mutated version like that found in familial ALS cases. The researchers also marked the mitochondria in the mouse neurons with a small fluorescent protein known as GFP. The GFP-tagged mitochondria would be easily visible under the microscope, allowing the team to track what happens over the course of the study.

At the start of the work, both the newborn SOD1 mutant mice and the control mice had identical gaits and motor control. Changes became apparent in the motor neurons of the SOD1 mutant mice after 4.5 months. Their mitochondria were larger and nearly circular.

By the time the SOD1 mutants were 10 months old, the mice had fewer mitochondria. What mitochondria remained were abnormally clustered in different areas of the motor neuron axon; in normal mice, mitochondria were distributed evenly along the axon.

Mitochondrial changes and SOD1 buildup occurred before the mice showed ALS symptoms, and these cellular changes grew more pronounced in tandem with worsening illness. In earlier studies, Vande Velde and colleagues had concluded that an accumulation of mutant SOD1 on the surface of mitochondria damaged the organelles and caused them to change shape and cluster together.

This study, however, showed that these changes in mitochondrial shape and distribution go on to affect the natural movement of mitochondria to the places that they’re needed, namely within the axon. Without fully functioning mitochondria, motor neurons don’t have the available energy they need to send and receive signals, which can ultimately cause them to wither and die. This misdistribution of mitochondria may be the main driver of the neuron damage seen in ALS, the researchers said.

What This Means

Although inherited SOD1 mutations cause only a small minority of all ALS cases, researchers believe that changes to SOD1 play a role in many cases of ALS. “Misfolded SOD1 is relevant to sporadic cases of ALS,” Vande Velde said, especially in light of new research that found the same buildup of mutant SOD1 in the motor neurons of sporadic ALS patients.

Researchers hope that developing pharmaceuticals to block the unnatural deposits of mutant SOD1 on mitochondria will prevent the progression of ALS. One such drug (Olexisome) is currently being used in clinical trials in Europe.

“Having misfolded SOD1 around is really not a good thing,” Vande Velde said, especially for mitochondria. Efforts to get rid of the mutant protein, she adds, may benefit ALS patients.

– Carrie Arnold