Sunday, November 21, 2010

Head and Shoulders, Knees and Toes...

Part 1:

If you found out that you were going to lose the use of your arms and legs in the next two years what would you do?
  ALS, more commonly known as Lou Gehrig’s disease, is one of the most common neurodegenerative diseases and is characterized by the death of motor neurons. Motor neurons are cells located in the brain and spinal cord that send out long projections and control your muscles, sort of like the electrical wires of the body. If these wires are removed, muscles in your body won’t get the message to move. This means that those diagnosed with ALS experience a progressive paralysis, losing the use of their bodies one part at a time. Every year 1 in 100,000 people are affected by ALS; slowly losing their independence, unable to walk, speak, or even express emotion through facial expression while still fully aware of their surroundings, trapped in a body that won’t listen to them.  Eventually, usually within 2-5 years of diagnosis, patients die from respiratory failure because the motor neurons controlling the muscles that help you breathe die as well.  This devastating disease can affect anyone. Although the usual onset of ALS is between 40-70 years of age a small proportion of ALS sufferers experienced symptoms, like the great Stephen Hawking, in their early twenties. It is twenty percent more common in men than in women however the incidence is more equal among men and women with increasing age. 

The cause of ALS is still a little unclear and is thought to be a multifactorial disease and so research has investigated several disciplines such as inflammation, excitotoxicity and cell-cell communication. While only 10% of ALS cases are familial, meaning the cause can be linked to defects in your genes, 90% of cases are sporadic, however there is a silver lining to this. When we look at nervous tissue taken from ALS patients, the common characteristic we find between both familial and sporadic cases is the presence of protein clusters called aggregates. By studying familial cases and the genes involved in ALS, we can generate models that allow us to investigate the mechanisms behind ALS and what makes motor neurons particularly vulnerable to protein aggregation. 

In normal cells, proteins initially come out as a string that must be folded properly to function. When these proteins are misfolded either under cell stress or as part of a disease pathway, they tend to stick to each other and form clumps or aggregates in the cell, which interfere with various cell processes and, if not taken care of, will lead to cell death. Whether protein aggregate formation is the beginning or the end of the pathogenic pathway involved in ALS, it is clear by experimentation that motor neurons don’t like having aggregates in them, and so a lot of ALS research has been focused on trying to understand the role aggregate formation plays in the pathogenesis of ALS.  In the next segment we will discuss current research, which explores the cell’s responses to these aggregates and possible explanations why motor neurons specifically show aggregate formation in patients with ALS. Stay tuned!

Michael Tibshirani
McGill University

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