Posted on behalf of Amanda Mascarelli
A rare, devastating neurodegenerative disease called ‘autosomal recessive spastic ataxia of Charlevoix-Saguenay’, or ARSACS, has been traced to defects in neuronal mitochondria, the power plants of cells. Researchers presented the results on 6 December at the annual meeting of the American Society for Cell Biology in Denver, Colorado.
The ARSACS disorder primarily affects the cerebellum, a part of the brain that plays an important role in movement. It was first described in the 1970s in descendants of a tiny population of French immigrants who settled in the Charlevoix and Saguenay River regions of Quebec in the late 1600s. Incidence of the disease in this ‘founder” population is around 1 in 1,500-2,000 – far higher than in the general population.
Unlike more common neurological diseases such as Alzheimer’s and Parkinson’s, which appear later in life, ARSACS strikes at an early age — showing up in toddlers just as they are learning to walk. Symptoms worsen over time, leading to poor motor control, uncoordinated eye movements, slurred speech, and muscle atrophy. Those with the disease are typically wheelchair-bound by their early 40s; most do not live past their 50s.
In 2000, researchers identified a single gene associated with the disease, called the ARSACS gene, which produces a massive protein called sacsin. But the role of the sacsin protein has been unclear. Since then, scientists have found some 100 distinct mutations in the ARSACS gene in people from more than a dozen countries.
Now, an international team of researchers has linked these mutations to a dysfunction in the mitochondria of neurons. By studying neuron-like cells in culture as well as in a knockout model mouse that they created, the group found that loss of the sacsin protein or errors in the protein message results in impaired mitochondria. This in turn leads to misshapen and disorganized dendrites, which are the branches of neurons that receive signals from other cells. In the knockout mouse, these disruptions led to cell death in the cerebellum, suggesting that this is the basis for the neurodegenerative impairments suffered by ARSACS patients.
Mitochondrial dysfunction has also been implicated in Parkinson’s disease, Alzheimer’s, and Huntington’s disease, suggesting a common link. “There are huge efforts there which can now possibly be informative for this rarer neurological disease because now we know there are some commonalities between the diseases,” says Peter McPherson, a cell biologist based at McGill University in Montreal, Quebec, who is one of the leaders of the effort.
Image: Neurons in a tissue culture were stained with an antibody that recognizes sacsin (red) and an antibody that stains mitochondria (green). Yellow shows where the two occur together, revealing a strong association between sacsin and mitochondria.