The Dr. Jekyll and Mr. Hyde of ALS

Ice bucket challenges were dominating all of our Facebook feeds a couple of weeks ago with people showing appalled shock as they dumped ice water on their heads.  It seemed like such a silly craze to me.  Why not just donate instead of putting yourself through this momentary misery?What this challenge did by stepping away from the more conventional “Walk to end…” campaigns was gain an immense amount of visibility and awareness for ALS.  Largely contributing to its success was the heavy involvement of celebrities (see the Youtube clip above….my particular favorite is Dave Grohl around the 2 minute mark!).  It proved to be an insanely successful campaign raising $113.3 million as of September 15, 2014, this for an organization whose annual budget is generally around $25 million per year.

The disease at the center of this campaign is ALS or Amyotrophic Lateral Sclerosis, a neurodegenerative disease affecting the motor neurons in the body.  Only about 10% of cases of ALS are hereditary, and the rest are sporadic.  Sensory nerves are not damaged during ALS keeping the ability to see, hear, and feel in tact.  Towards the end of disease progression,  massive death of motor neurons traps patients in their bodies making them incapable of functions that the mind is still capable of imagining.  Disease onset begins between the 40s and 70s and progresses quickly with most patients dying due to respiratory failure within 3-5 years of symptoms occurring.

Scratching an itch, hitting the snooze bar, going for a run: these are all actions that depend on your motor neurons. For a muscle to move, a message needs to be transported from the brain to the spinal cord and then from the spinal cord to the muscle (see figure below).  These messages are transported on nerve cells.  During ALS, these nerves cells die and are no longer able to communicate with the muscles.  Without communication from the nerve cells, the muscles eventually wither away.Slide3

The role of the immune system in ALS is an area of lots of research and the results are oftentimes conflicting. Many different immune cells play a role in the progression of this disease but much of the focus has been on microglia, brain-resident macrophages (a broad category of cells literally meaning “big eaters”).  These cells are normally very helpful and supportive to nerve cells providing growth factors (nourishment) to keep them healthy and happy. Another role of microglia is to clean up after a cell has died as happens with nerve cells in ALS.   This process of “taking out the trash” is important in restoring a healthy state after injury.  By getting rid of these dead nerve cells in early stages of the disease, microglia provide a protective effect on the living motor neurons.  As the disease progresses however, microglia basically go from being Dr. Jekyll to Mr. Hyde.  (Go to the nerd boost for more information about this!)  Mr. Hyde microglia start to release inflammatory cytokines and other toxic substances that can directly kill the motor neurons causing progression of the disease.

Immune cells aren’t all bad during ALS though.  One subset of cells called Regulatory T cells makes an attempt to control inflammation at early stages of the disease.  These T cells are a component of the adaptive immune system and normally help to keep inflammation in check.  One of their main roles is to prevent autoimmune diseases from occurring…they prevent other immune cells from attacking your tissues.  When Regulatory T cells are recruited to the brain and spinal cord during ALS, they can help microglia to be more Dr. Jekyll than Mr. Hyde.  They might also be able to directly help nerves to survive.  At later stages of the disease however, these Regulatory T cells are no longer able to control the inflammation or the death of the motor neurons.

The immune component of ALS is a reaction to an initial problem with the motor neurons dying so there are definitely components of the disease that are not immune-mediated.  But figuring out how to prevent microglia from becoming Mr. Hyde or how to enhance the recruitment and activity of those Regulatory T cells are potential targets for future therapeutic options to slow or halt disease progression.

To learn more about ALS and/or to participate in the ice bucket challenge, go here.

Sources for this articles can be found, here, here, here, here, and here.



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