Science: Under the Microscope - Worth the battle


I WAS amazed to come across a Peanuts cartoon in which Charlie Brown is informing strident know-all Lucy that he plans to enter a spelling competition. Lucy scoffs at the idea: but Charlie Brown is ever the optimist. What is the point of life if you don't try? Witheringly, Lucy challenges him to spell acetylcholinesterase. The final frame shows a crumpled Charlie despondently reflecting: "Maybe I shouldn't enter."

In my research, I too have felt defeated by acetylcholinesterase, not by its jaw-breaking pronunciation or its spelling, but by attempts to understand what it is doing in the body, in particular in the central nervous system.

At first glance, acetylcholinesterase appears simple enough. It is an enzyme, responsible for degrading a well-known chemical messenger (acetylcholine), thereby terminating the signal that can be passed from certain brain cells (neurons) to others. Acetylcholine also acts as the link for nerves (motorneurons) to cause the contraction of muscle, and hence underpins all movement. By curtailing this, acetylcholinesterase is of pivotal importance to body function. But then so are many other chemicals. The reason that this one might be edging into public consciousness more than other enzymes, is that it is the target of two very different types of drug.

The first class of now infamous compounds that work through this seemingly innocuous enzyme, are the nerve gasses, such as Sarin, DFP and Soman. These agents block the normal action of acetylcholinesterase, irreversibly. The consequences are that the transmitter acetylcholine, now escaping degradation, will start to accumulate. Why is this increase so pernicious?

It may not be as obvious as when you move an arm or a leg but the very act of breathing is also based on the signal from a nerve (the phrenic nerve) to a muscle (the diaphragm). So every breath you take depends on minute amounts of acetylcholine being released from the nerve to the diaphragm, and then being inactivated by acetylcholinesterase. When the enzyme is unable to do its job, and the transmitter levels increase, events take a lethal turn. Large amounts of acetylcholine paradoxically cause a block in the transmission of the signal, by jamming the normal mechanism. Hence nerve gasses, by working on acetylcholinesterase, will indirectly prevent respiration, and thus, in the absence of an antidote, cause death very rapidly.

But less dramatic and long lasting inactivation of acetylcholinesterase can be harnessed for therapy, this time in Alzheimer's disease. The most established treatment of Alzheimer's is a drug which acts within the brain to reduce the effects of acetylcholinesterase, and thus enhance the availability of acetylcholine. This strategy is considered desirable because it is known that certain neurons that use acetylcholine as a transmitter, are particularly prone to degeneration in Alzheimer's. Unfortunately, however, this treatment does not prevent the inexorable loss of cells that characterises this tragic condition.

The problem is that not all neurons lost in Alzheimer's use acetylcholine: however, these vulnerable cells do, surprisingly, contain the enzyme. Why? For years now it has been suspected that acteylcholinesterase might have a second function, an alter ego not involving acetylcholine, but one which may or may not be important in neuro-degeneration. The problem is trying to find out exactly what that second function is. Unlike Charlie Brown, I am not going to let acetylcholinesterase get the better of me.

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