New Hypothesis: Parkin causes Parkinson's Disease via Downregulation of Akt Signaling

Neurodegenerative diseases, including Parkinson's, were for many years regarded as exclusively diseases of molecular crud. You would look at brains of patients with Alzheimer's and Parkinson's patients and notice that there were all these aggregates of protein crud forming in specific locations. This led scientists to conclude that the crud must be causing the neurons to do die through a mechanism that was not at the time clear.

The reality we are learning is far more complicated.

There is a form of inherited Parkinson's disease that is caused by loss-of-function mutations in the gene Parkin. For a while, we didn't know what Parkin did, but it was eventually discovered that Parkin is what is called an E3 ligase. E3 ligases are proteins that attach tiny protein tags called ubiquitin to other proteins. You can think of ubiquitin as a little tag on a protein that says that it is old and needs to be destroyed. Ubiquitinated proteins are taken to a complex called the proteasome where they are degraded. Thus, E3 ligases are involved in the process of regulating protein turnover.

When people heard that Parkin was an E3 ligase, they were like "Hey, that makes sense. Parkinson's has a lot of protein crud lying around. Maybe if you lose Parkin then you don't get rid of that crud."

This paper -- I will get to it in a second -- shows that there is more to it than that.

It turns out that ubiquitin also regulated protein signaling, particularly growth factor signaling. There is a receptor in the brain called Epidermal Growth Factor Receptor (EGFR) which responds to the growth factor Epidermal Growth Factor (EGF). EGF signaling activates pathways in neurons and other cells that result in signals to proliferate using a pathway called the MAP Kinase pathway (MAPK) and to survive insults or genetically programmed cell death through a pathway called the Akt pathway (Akt). The EGFR receptor is on the surface of the cell, and when it binds EGF it activates both these pathways. (It is insanely more complicated than this but it will have to do.)

Ubiquitination regulates how long EGFR stays on the surface to signal. When it binds EGF, other proteins come by to ubiquitinate it and internalize it preventing further signaling. Ubiquitination and internalization are a mechanism for limiting the signal from EGF. Therefore, ubiquitination in this case also functions to regulate signaling.

Which brings us to the specific case of Parkin, as described in a recent Nature Cell Biology paper by Fallon et al. Fallon et al discovered that the gene Parkin regulates Akt signaling through an interesting mechanism. They discovered that Parkin ubiquitinates an adaptor protein that normally binds to the EGFR, a protein called Eps15. Eps15 is a protein that binds ubiquitin and regulates the internalization and degradation of EGFR.

What happens is rather clever. When EGFR signaling is begun, Parkin comes along an ubiquitinates Eps15. Then Eps15, instead of binding and causing the silencing of EGFR, binds to itself and falls off of EGFR allowing signaling to persist. EGFR activates MAPK and Akt causing the cell to be happy and multiply.

Say you don't have Parkin. Well then Eps15 stays attached to EGFR causing it to be degraded, lowering Akt signaling.

Here is a diagram from the Supplementary Information of the paper that describes the process (click to enlarge):

What would be the overall effect of Parkin loss and the resulting decrease in Akt signaling. Well it could explain the very specific death of neurons that characterize Parkinson's disease. Parkinson's patients lose a very tiny body of cells in an area called the substantia nigra. These cells maybe small in number, but they are secrete dopamine and are responsible for regulating voluntary motion. Perhaps the loss of Parkin is causing these cells to lose Akt-mediated signaling that is required for their survival.

This paper is interesting to me because it demonstrates a couple of things:

• 1) In line with my one philosophical principle: Things are always more complicated than you think.
• 2) We are beginning to understand more and more that neurodegenerative diseases are not just diseases of molecular crud. The disease is caused by specific changes in signaling. Any treatments that we can invent need to take that into account.