Defective cell ‘battery’ plays central role in neurodegenerative disease

Posted on Thursday, January 26, 2012

The Neuro’s Dr. Peter McPherson co-led the recently puplished research on ARSACs. / Photo: Owen Egan

By Anita Kar

New research out of the Montreal Neurological Institute and Hospital has traced a devastating neurodegenerative disease that first appears in toddlers just as they are beginning to walk to defects in mitochondria, the ‘batteries’ or energy-producing power plants of cells.

The disorder, Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS), primarily affects the cerebellum, a centre for movement coordination in the brain. ARSACS was first identified in the late 1970s in a large group of patients from the Charlevoix and Saguenay regions of Quebec. The incidence of ARSACS in this ‘founder’ population is 1 in 1,500-2,000 births, with a high carrier rate of 1 in 23. ARSACS strikes at an early age. Symptoms, which worsen over time, include poor motor coordination, spastic stiffness, muscle wasting, uncoordinated eye movements and slurred speech. Most patients with the disease are wheelchair-bound by their early 40s and have a reduced life expectancy.

ARSACS is not unique to French-Canada as scientists have found over 100 separate mutations in people worldwide including Japan, Turkey and across Western Europe.

The research significantly increases understanding of the disease and reveals an important common link with other neurodegenerative diseases, providing renewed hope and potential new therapeutic strategies for those affected around the world.

“This finding is the first important advancement in the 10 years since the identification of the mutated gene,” said Dr. Bernard Brais, neurologist at The Neuro.

In 2000, scientists identified the gene associated with the disease, called SACS, which produces a massive 4,579 amino acid protein called sacsin, but until now the role or the function of the sacsin protein has been unknown. The multi-institutional collaborative research led by Drs. Brais and Peter McPherson at The Neuro and Paul Chapple at Queen Mary, University of London, indicates that that the sacsin protein has a mitochondrial function, and that mutations causing ARSACS are linked to a dysfunction of mitochondria in neurons.

“By studying neurons in culture as well as in knockout mice (which do not produce sacsin), the team found that loss of the sacsin protein results in abnormally shaped and poorly functioning mitochondria,” said McPherson. This disruption led to defective changes in the neurons and eventual death of the neurons. In the knockout mice, these disruptions led to neuron death specifically in the cerebellum, suggesting that this is the basis for the neurodegenerative impairments suffered by ARSACS patients.

“Mitochondrial dysfunction has also been identified in major neurodegenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s diseases,” said McPherson. “This common link means that research being done on a large-scale on these other diseases may prove critically informative to rarer neurological diseases such as ARSACS, and the inverse may be true, our findings may be fundamental to the study and treatment of other neurodegenerative diseases.”

 

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