The Highway to Neurodegeneration: why your brain needs a proper mechanic
Imagine that you made a huge investment and bought the car of your dreams. You get the oil changed regularly, you keep the perfect amount of air in the tires, you keep it clean, and you do your best to properly maintain it – at least initially. For many, carelessness ensues and one-by-one those pesky symbols on the dash all start to light up in a futile reminder that an oil change is overdue, or that the battery or engine needs servicing.
That is, until one day the car doesn’t start.
This dreadful scenario is similar to the progression of degenerative diseases such as Alzheimer’s and Parkinson’s disease within the human brain.
Like a car, neurons – the fundamental functional unit of the brain – require proper maintenance to function properly. The average brain contains over 86 billion neurons and to keep them running like a well-oiled machine, check-ups and maintenance must be done regularly. In the brain, neuronal maintenance is carried out by supporting cells called microglia. There are roughly 17 billion microglia within the brain that carry out countless actions such as cleaning up cellular waste and ensure neuronal connections are properly functioning – similar to how a car owner maintains their vehicle.
Think of your busy life as a microglia that constantly juggles an extremely long to-do list. Car maintenance is also on that to-do list and as other tasks and responsibilities develop; car maintenance may slowly decline in importance. In the brain, when microglia become preoccupied with other jobs, neuronal maintenance suffers, contributing to the development of degenerative diseases like Alzheimer’s or Parkinson’s disease. Research at the University of Western Ontario published in the journal Cell Death and Disease (2015) described just how microglia communication may negatively affect developing neurons and possibly lead to degenerative disorders.
Specifically, in the healthy brain, a major role of microglia is to maintain minimal levels of inflammation, which allows neurons to function properly. However, if microglia produce too much inflammation, neurons lose their ability to function properly and degenerative diseases develop. Importantly, how neurons respond to excessive inflammation, especially during proper brain development, had not been shown – until now. Just like neglecting to take a car in for a tune-up puts unnecessary stress on the vehicle, the inflammation produced by microglia puts unnecessary stress on neurons. Dr. Sean Cregan led this research study as it uncovered just how developing neurons respond to the excessive amount of inflammation that microglia may produce.
Just as low oil levels in your car result in a “check oil” light to flash on the car dash, excessive amounts of inflammation produced by microglia cause neurons to make a protein called p53. In neurons, the production of p53 is an attempt to combat cell stress and administer cellular repair, however it may also trigger cell death if repair is unsuccessful. Consider this protein equivalent to a “check oil” light because if it is not accurately tended to, it will lead to more severe warning signals to turn on, like the “check battery” or “check engine” lights.
Importantly, the involvement of p53 in stressed neurons may be related to why neurons degenerate in Alzheimer’s disease and Parkinson’s disease. Therefore, to examine how p53 in developing neurons can lead to neuronal stress, these researchers wanted to see what would happen in an inflammatory environment if this “check oil” light was not present in isolated mouse neurons. Cregan and colleagues determined that developing neurons without the protein p53 could not turn on these more severe warning lights that would induce a detrimental chain reaction. Within the neuron, these more severe warning lights correspond to two other proteins called p21 and PUMA that each carry out specific functions within neurons. For instance, p21 may be equivalent to a less severe “check battery” light as certain functions within the neuron may only stall for short periods, while on the other hand, PUMA may be equivalent to the more severe “check engine” light that may result in the death of a neuron. Therefore, the inflammation produced by microglia cause neurons to generate the protein p53 that results in the production of both p21 and PUMA, which decreases neuron function and causes neuron death, respectively. Importantly, in an overly inflammatory environment, neurons lacking p53 maintain their proper function. In other words, the neurons strangely do better if they ignore all the signs telling them that inflammation is present and keep going about their daily business. These findings suggest that p53 has potential to be a therapeutic target for treating degenerative diseases such as Alzheimer’s disease and Parkinson’s disease.
Understanding how specific cell pathways affect the ability of neurons to properly function is crucial to understand neurodegenerative diseases with no known cause or cure. Neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease are associated with increased inflammation and increased neuron loss. Therefore, studies that uncover a novel understanding in how excessive inflammation produced by microglia can harm neurons in the brain may be the first step to uncovering therapeutic targets for these degenerative diseases.
Original Research Article:
Guadagno, J., Swan, P., Shaikh, R. et al. Microglia-derived IL-1β triggers p53-mediated cell cycle arrest and apoptosis in neural precursor cells. Cell Death Dis 6, e1779 (2015). https://doi.org/10.1038/cddis.2015.151