Common Cause?

A sensational bit of news has begun spreading across the ALS Community: A common cause for all forms of ALS has been found!

But has it? Certainly it is a common process but is it really the cause?

The process involved is autophagy. One of the important jobs of autophagy is to break down and recycle misfolded (improperly constructed) proteins marked by another protein called ubiquitin. A proteasome then breaks down the protein into amino acids which are then used to build new proteins It's like tearing a house apart, timber by timber, and reconstructing another from the material. If this process is interrupted or incomplete then you have a pile of junk left laying around which is thought to impede the efficient operation of the cell. An example of this is the amyloid plaques that are thought to cause Alzheimer's. However, removal of those plaques did not affect disease progression.

ALS is now strongly considered to be a "non-cell-autonomous" disease. This means that something outside the cell is causing the disease. Some of the most persuasive evidence for this is a recent study involving cells known as astrocytes become toxic to the motor neurons. This happens in both the inherited form (familial or FALS) and the more common sporadic form (SALS). Previous readers will know about my interest in current research regarding neuroinflammation as a primary cause of ALS and other neurodegenerative disease. This is also a common cause from a variety of triggers. It is, however, upstream of the "cause" identified in the recent news.

The calcium influx from the excitotoxicity created by neuroinflammation damages the mitochondria. In fact, this is a primary event. It is known that the motor neurons "die-back" along the axon, and that mitochondria motility down the axon is one of the first problems in ALS and neuroinflammation models. Once the mitochondria are damaged and cannot be repaired/replaced, pretty much all bets are off inside the cell. The cell becomes starved for energy, the cellular machinery (such as proteasomes) begins to fail, and the mitochondria start producing apoptotic factors which leads to cell death. Normally this wouldn't be a problem as many of the cells in the human body die and are simply replaced (even brain cells). However, the motor neurons you are born with are the very same motor neurons you die with.

I therefore posit that this "common cause of ALS" is too downstream of the actual cause for treatment based solely on it to be effective in and of itself. It's like trying to stop a waterfall at the edge of the cliff rather than building a dam in the stream a mile further behind. I do believe that although this may not lead directly to a single effective treatment, it would nearly certainly be an important part of a "cocktail therapy". The major positive I take away from this is that it answers the question whether the SOD1 model is applicable to all forms of ALS.