Hmm…that title was a bit far-fetched. It was supposed to play off the adage “Don’t judge a book by its cover”. Regardless, I will get to my point: new research Parkinson’s disease has revealed a fascinating connection between seemingly unrelated proteins.
Parkinson’s disease is a long-term disease characterized by motor neuron degeneration, but in late stages also causes dementia (the picture below is from an 1886 book on neurological diseases). The motor symptoms result from the death of cells in the substantia nigra, a portion of the brain involved in movement and motor planning. The result of this is lowered levels of dopamine within the substantia nigra.
While the exact cause of the degeneration is unknown, years of research has been placed on the Lewy-bodies (congregations of proteins) that form within cells. Patients with Parkinson’s have an elevated level of these Lewy-bodies in their neurons, so it is natural to assume they play an important role.
A very prevalent protein involved in the formation of Lewy-bodies is α-syneuclein, the long, stringy protein pictured below. This protein’s main role in human cells is only vaguely understood (though it seems to be important in managing the bird songs of zebra finches). It is possible that the protein is an inhibitor of phospholipase D2, which means that more of this protein would result in lower levels of phosphatidic acid and choline, which are neurotransmitter precursors.
The way α-syneuclein accumulates into Lewy-bodies is through a process called aggregation. If the protein gets phosphorylated (usually this means “marked for degradation”) when it is not supposed to, it can clump with others to form these aggregates. Even further, the “prion effect” is seen with this phosphorylated protein, meaning that if it runs into healthy proteins, it can change them into unhealthy proteins, compounding aggregation.
So how do these healthy α-syneuclein’s get phosphorylated into their unhealthy versions in the first place? The answer may lie in GRKs.
Acronyms are great, aren’t they? GRK stands for G-protein coupled receptor kinase, which is a collection of words that essentially means “cell receptor deactivator”. These enzymes cycle through a cell and find cell receptors that are being activated too often. Since the cell no longer wants these activated, the enzyme phosphorylates it, which marks the receptor for death.
Here we again see the word “phosphorylates”. It was just this process that began the aggregation of α-syneuclein into Lewy-bodies. Recent studies have shown that these GRKs are able to phosphorylate α-syneuclein even though their structures insist that they should not. Prior to this research, there was no reason to believe that a GRK would play a role in Parkinson’s disease, as the enzyme regulates pathways quite unrelated to aggregation of proteins.
But here we see it, an enzyme phosphorylating a protein that its structure insists it should not. This is precisely where the title of this post fits in. It is so easy for researchers to think that they know everything and skip over some ideas because they believe them to be invalid.
In the end, however, research needs to be thorough for its own sake. The world works in very mysterious ways sometimes, and we need to check even the most remote possibilities if we are indeed set on learning more about this universe. Perhaps Parkinson’s disease may be cured because a few people decided to observe the effect of a random enzyme on α-syneuclein, even though the science told them they shouldn’t.
Don’t Judge an Enzyme by Its Structure
