Visitor counter, Heat Map, Conversion tracking, Search Rank

This page presents a hypothesis on the mechanism of ALS that I have been playing with since I learnt that misfolded SOD1 has a tendency to stick into the VDAC1 channels. Neil Cashman's discovery of prion-like propagation of wild-type SOD1 was another piece of the puzzle.

 

The reasoning goes like this:

 

For some reason (which is irrelevant here) a certain amount of misfolded SOD1 enters a cell via exocytosis.

Some of it sticks to the VDAC1 channels and disturbs ADP feed into the mitochondria causing reduced production of ATP via phosphorylation.

Lack of ATP makes it more difficult for endoplasmic reticulum to maintain correct Ca2+ levels, causing problems in the protein folding process. More and more of the more sensitive proteins (such as TDP-43) are misfolded.

ER  stress causes TDP-43 to migrate from the nucleus into cytosol.

The amount of misfolded TDP-43 overwhelms the cleanup machinery and starts to aggregate. Some of the misfolded SOD1 is released from the cell and enters neighboring cells via exocytosis.

In the case of a motor neuron, the TDP-43 aggregates block the axonal transfer and the cell is eventually destroyed.

 

This hypothesis is just that - a hypothesis; i.e. a framework to try to use as a glue between different observations. I do not claim that this would actually be the mechanism behind ALS - it is just a thought experiment of what might be possible.

 

There is also a mindmap explaining what was written above.