“U” marks the spot.

Subject areas: Cell Biology, Infectious Diseases

Vocabulary:  Ubiquitin – a molecular tag inside of cells that labels components for destruction in order to get rid of malfunctioning or non-functioning parts.

Parkinson’s Disease – a neurodegenerative disease which primarily affects motor function initially, causing shaking and tremors in movements.  There is substantial cell death of neurons in the substantia nigra region of the brain.

Autophagy – literally, eating oneself (auto = self, phagy = eating).  In this case, refers to cells destroying internal parts of themselves, such as mitochondria.

The article: Manzanillo, P.S.  et al.  Nature (2013) doi:10.1038/nature12566

If you have ever gone out into parks or forests and seen a spray-painted mark on some of the trees, chances are a forester or park ranger marked the tree for removal, usually for the overall health or safety of the forest or area.  Inside every one of our cells, we have a similar system.  Over time, the proteins and other components that our cells make to stay alive and functional will “wear out” or degrade.  Rather than have non-functional or malfunctioning parts floating around inside the cell, they get tagged with a molecular tag that targets them for destruction.

That molecular tag is ubiquitin.  The tagging molecules are enzymes called ubiquitin ligases.  A ligase is just what we call enzymes that join things together.  There are different ubiquitin ligases that join ubiquitins to different molecules in different circumstances.  As it happens, ubiquitins can not only be used to label molecules, but also organelles inside the cell also – usually little membrane-bound “balloons” of stuff that need to be broken down.

Now let’s change subjects for a minute.  If  infectious organisms get into your body, the immune system goes into action to isolate and destroy them.  Part of that immune response is for macrophages (a kind of white blood cell) to phagocytose the infectious organism – surrounding it, then pinching it off inside a membrane-enclosed bubble that heads inside the cell where it gets tagged for destruction.

In this article, the authors demonstrate that parkin, a type of ubiquitin ligase, is used to destroy some intracellular pathogens, such as Mycobacterium tuberculosis, which can cause tuberculosis in humans.  They do this, in part, with a nifty set of experiments in which they infect a culture of mouse macrophages with M. tuberculosis, and observe what happens to the bacteria – where do they go, do they live, die, reproduce.  The nifty part is that they use regular macrophages, macrophages that are mutated so they do not have functional parkin, and macrophages that are mutated to make extra parkin.  The hypothesis was that cells without parkin will not destroy the bacteria properly, and will allow more bacteria to live and reproduce; meanwhile, cells with extra parkin should have fewer bacteria than even the normal cells (which do not kill off all of the bacteria in the first place).  That is exactly what they saw in their experiments.

Here’s a cool twist to the story.  Parkin is so named because mutations in the gene that encodes parkin have been linked to development of heritable early-onset Parkinson’s disease.  It is not clear at this time how exactly parkin contributes to normal neuronal function or how mutated versions lead to Parkinson’s disease.  What is known is that it seems to be related to maintaining mitochondria.  Mitochondria are the organelles that produce energy for the cell.  They are crucial for the health of the cell.  Parkin seems to be involved in both fission of mitochondria (they split into two to produce more), but also in tagging mitochondria for destruction.  It is unclear yet how these functions fit together, and what they have to do with Parkinson’s disease.

One possibility is that parkin helps cleanly get rid of damaged or malfunctioning mitochondria before they start to leak their internal contents.  This could help cell survival because leaky mitochondria can trigger programmed cell death.

Another interesting piece of the puzzle is that mitochondria are believed to have evolved from a bacterium that was phagocytosed, not digested, and turned out to be a helpful partner to the cell.  Over evolutionary time, the mitochondria lost large parts of its DNA (but not all), so that it could no longer encode a complete independent organism.  By that point, it was just an organelle within eukaryotic cells.  Still, the similarity in how it can be managed by parkin and how some bacteria are also tagged suggest interesting parallels.

This is an example of the early stages of what could be very exciting research.  It is not a huge breakthrough yet, there is no cure for Parkinson’s yet, but there is the tantalizing possibility that it could play in important role.  There are still a ton of questions that need to be answered in order to make sense of the data and come up with functional pathways for normal or pathological cells.  It could be very helpful and interesting to look at parkin from two quite different viewpoints: pathogen destruction in macrophages, and mitochondrial maintenance or destruction in neurons.  It is very likely that what is learned in one system could be applicable in some way to the other.

 

By admin in BioNews on September 5, 2013