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

"Parkinson's Disease: Working Towards a Cure": Part 1-- The Basics

This is the first post from a three part series written by Andrew Greene, a graduate student at McGill University studying Parkinson's Disease. 

James Parkinson was a British apothecary-surgeon best known for his medical report entitled "An Essay on the Shaking Palsy." Published in 1817, it was a detailed description of the disorder that would one day be known as Parkinson's disease. The disease can bring on a variety of symptoms, many of which we're only just beginning to appreciate, but the best understood are the movement related effects. Typical symptoms include tremors of the limbs and difficulties performing movements, especially ones that have multiple parts, such as reaching out to a cup, grabbing it, and bringing it to your lips. There is presently no cure for Parkinson's disease, but there are a number of treatments available to at least temporarily alleviate the symptoms, and these will be discussed in detail in part 2.
Despite the fact that Parkinson's disease is primarily a movement disorder, the muscles themselves generally remain healthy. It's actually a part of the brain involved in coordinating movement that has traditionally been said to be most prominently affected by the disease. This part of the brain is called the substantia nigra, which means black substance, referring to its characteristic dark colour compared to surrounding brain regions. The substantia nigra is located near the center of the brain and contains neurons that secrete a chemical called dopamine. Dopamine is a type of neurotransmitter, which are a class of chemicals that neurons emit in order to communicate with each other.
Dopamine is best known for its role in the brain's reward system, in which it's used to provide feelings of pleasure and enjoyment in response to things such as food, sex, and certain drugs. However, dopamine released by the substantia nigra also plays a critical role in modulating the activity of the striatum, a brain region that is essential in planning and coordinating movements. The striatum is the origin of two neural pathways that exert opposite effects on movement. The first of these is the so called direct pathway, which is thought to facilitate and reinforce intended movements. The second is the indirect pathway, which is thought to be responsible for inhibiting unwanted or inappropriate motion. Dopamine released by the substantia nigra helps maintain a balance between these two pathways by increasing the activity of the former and decreasing the activity of the latter.
In Parkinson's disease the dopamine-emitting neurons of the substantia nigra die off, which tips the delicate balance between the direct and indirect pathways. The result is too much activity in the indirect, motion-inhibiting pathway and too little in the direct, motion-facilitating pathway, which ultimately makes it exceedingly difficult for a patient to move. Why dopamine-emitting neurons of the substantia nigra die in Parkinson's disease is not known, though research over the last few decades has gone a long way towards solving the mystery, as we'll see in Part 3. Uncovering the reasons for their death is the first step in learning how to stop these neurons from dying, leading to better treatments and hopefully even a cure.

Stay tuned for Part 2: Current Treatments and Part 3: Towards a Cure. Coming soon!