by Brooke Napier
Apoptosis is programmed cell death. It is controlled cellular suicide that is responsible for humans not having webbed fingers. Less dramatically this time - apoptosis effectively and efficiently removes extra and unnecessary cells during development.
Cellular proteins called caspases control apoptosis. Caspases are a family of proteins known as cysteine proteases and they mediate cell suicide by forming protein complexes with activating complexes in the presence of adaptor proteins. They cleave other caspases and other cellular substrates to orchestrate a very controlled cellular destruction.
Humans encode 11 caspases, and while most of them dedicate their folded-life to carrying out apoptosis, some caspases have been known to dabble in immune regulation (ex: containing inflammation during infection to the site of infection) and spermatogenesis (you’ll have to ask a sperm-centric Ph.D. candidate about this one).
Although I have previously emphasized the importance of apoptosis/caspases in the development of our digits (I <3 my thumbs), ANTI-apoptotic molecules (members of the BCL-2 family) are extremely important during the development of the brain. There is relatively little turnover in the brain, so maintenance of differentiated neurons (peripheral neurons specifically) is very important.
Since apoptosis is specifically down-regulated in many neurons, one would assume that after development of the human brain caspase proteins are no longer needed in a healthy human. But then why have so many researchers found that caspases are required normal, everyday neural functions?
Caspases are serving a completely different function in the healthy adult human brain.
Ah ha! It turns out caspases can also dabble in other, very important neuronal functions. In fact there is data showing that activation of caspases in neurons can control normal neural physiology.
What are the new roles for caspases in neural physiology?
1) Dendritic pruning, or trimming the hedges, if you will. Dendrites (from the word tree in Greek) are beautifully branched neurons that transmit electrochemical stimulation from other neural cells to the soma, or cell body, of the dendrite, which then makes the executive decision to pass on the electrochemical signals to more dendrites via neurochemical synapses. This is the beautiful orchestra that is neuron-to-neuron communication in the nervous system.
Pruning of the dendrites is important for normal brain functions, it removes neglected or misguided dendritic branches, which would normally get in the way of forming fresh, new, sparkly synapses. Just like learning, the formation of our neural connections are fluid, and caspases grease the spokes. This mechanism of plasticity is as important as it sounds; Caspase 3 has been implicated in the zebra finch and fly models of learning and memory.
2) Axon guidance and synaptogenesis. Basically if you make a mouse that is caspase-deficient you have successfully made a mouse that has defects in axon targeting and synapase formation during development, which leads to significant developmental delays.
After poking my nose into this research, it seems like not a lot is understood about how caspases effect axon guidance or synapse generation – but there is preliminary data that suggests without some specific caspases axons show delayed/misguided maturation and some proteins required for synapse generation are impaired.
3) Normal synaptic physiology, turns out low levels of caspase 3 activation are required for synaptic changes that underlie memory.
Related, long-term depression (LTD), where synapses become less sensitive to stimulus (and the dendritic branches shrink or get eliminated), is associated with local activation of Caspase 3. Turns out, if you block caspase 3 or 9 activation you can effectively stop LTD! Follow the Figure legend below to learn more about this mechanism.
Too bad we can prescribe caspase 3 inhibitors for patients diagnosed with LTD (remember all the other things caspases do?).
The once infamous rapid-cell-death associated family of proteins has now relinquished its former title and should now be referred to as: Caspases: the we-can-help-you-learn family of proteins. In the words of Bradley Hyman and Junying Yuan:
“In addition to being a signal of acute, inexorable death, caspase activation in other circumstances (at least within the CNS) might instead be a pivotal event for responding to ever-changing environmental stimuli.”
Hyman, B., & Yuan, J. (2012). Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology Nature Reviews Neuroscience, 13 (6), 395-406 DOI: 10.1038/nrn3228