The science behind neurodegeneration

Saturday 26 May 2018

I've been reading quite a bit recently about the science behind neurodegenerative diseases. I find this stuff really interesting, though I appreciate that it may not be everyone’s cup of tea… but do please try and bear with me.

See also related posts little white pill for an overview of what Parkinson’s is, and faulty DNA for an introduction to the genetics of Parkinson’s.

The mobile phone in my pocket is a marvel of technology. My iPhone (which is far from the latest model) has more computing power than the original 1980s space shuttle. In fact, this is a massive understatement. The processor in my phone can execute more than a thousand times more calculations per second than all the onboard computers of the original space shuttle combined.

But despite its ability to interpret my spoken instructions to find the nearest Indian restaurant, play back all manner of digital media, and retrieve an answer to virtually any question I can think of, my phone has a flaw.

After nearly three years since I bought my smartphone, the electrodes in the lithium-ion battery inside are now coated with microscopic clumps of oxides that interfere with the flow of electric charge. In other words, the battery is knackered and needs to be frequently recharged.

Similarly, the human brain is a miracle of engineering – biological engineering. With its 100 billion neurons and 100 trillion synapses, it is still able to outsmart the smartest computer at simple tasks like understanding a newspaper headline or talking about the weather.

And, like my mobile phone, my brain has a flaw. A protein called alpha-synuclein is misfolding and gradually building up into sticky clumps known as Lewy Bodies in a tiny region deep in the centre called the substantia nigra (part of a structure called the basal ganglia). At the same time, the dopaminergic cells in this part of the brain that produce dopamine, an essential neurotransmitter, are dying. It is not yet proven that the cell death is caused by the build-up of alpha-synuclein in the cells, but it seems likely.

Interestingly, the story is similar in many other neurodegenerative diseases: proteins that normally perform a useful function start to misfold and form sticky clumps, more generically called amyloids. Like in the phone battery, these clumps keep on growing and there is currently no known way to stop them.

In Alzheimer’s, the rogue protein is beta amyloid. In a similar way to alpha-synuclein in Parkinson’s, the protein starts to build up into amyloid plaques that are a hallmark of the disease. These were only properly identified in the 1980s and again, they are suspected to be a causal factor in the disease though this is not yet proven and it is conceivable they are a by-product of some other mechanism.

The cause of Huntington’s (see my previous post on Huntington’s) is somewhat better understood. The culprit is a protein called Huntingtin which, due to a genetic fault in the gene of the same name, builds up an uncontrolled manner and also damages the basal ganglia, including the substantia nigra, hence this disease, like Parkinson’s, is a movement disorder.

In Creutzfeldt-Jakob disease (remember all the scare stories about “mad cow disease”?) there is the build up of misshapen proteins called prions which act like an infectious agent, triggering other proteins to also misfold and become toxic.

In a way, neurodegenerative diseases are like cancers. Rather than being caused by an external pathogen such as a virus or bacteria, they are probably the result of the body’s normal processes running out of control. Useful proteins occasionally misfold and lead to runaway growth of protein aggregates which, it is thought, then wreak havoc with normal neural function. The human brain is an astonishingly complex orchestration of neurons, axons, dendrites, cerebrospinal fluids, enzymes and neurotransmitters all in delicate equilibrium. In some ways it is surprising that things don’t go wrong with it more often.

This leads us to an interesting, and largely unanswered, question: to what extent does the brain (and body) have natural defence mechanisms to these rogue proteins?  And can these be exploited?

Autophagy (from the Greek for "self-devouring") is a relatively recently discovered process whereby cells can destroy dysfunctional components of themselves in an orderly fashion. For example, damaged mitochondria (energy producing structures) can be shut down so that they do not damage the whole cell. There is also the process of apoptosis or programmed cell death which, as the name suggests, is the orderly destruction of an entire cell for the greater good of the organism.

There is a growing understanding that both of these processes are commonplace. Like the lymphocytes in the immune system that continuously hunt and kill infectious agents, it appears that the processes of autophagy and apoptosis are constantly active: nipping in the bud malfunctions in normal cell operation before they become a bigger problem. So, for example, when autophagy is suppressed there is a greater risk of developing cancers.

One of several theories of the cause of Parkinson’s is that normal autophagy process has been inhibited in some way so that the rogue proteins build up faster than the natural defence mechanisms can clear them away and that dysfunctional mitochondria are not recycled, eventually causing cell death.

I am no neuroscientist and I do not have the time, nor the mental capacity, to assimilate all the literature on the subject, so my views are overly simplistic and probably incorrect. That said, my personal guess from what I have read is that there are several interlinked things going on in Parkinson’s:

(1) Alpha-synuclein has useful functions but occasionally misfolds and starts to build up into unwanted clumps that can damage dopaminergic (and other) cells.  The exact mechanism by which the cells are damaged is not fully understood though it may involve microglia (a type of cell that acts as the brain’s immune system) becoming overactive and causing inflammation.

(2) Mitochondria in the dopaminergic cells sometimes malfunction

(3) Autophagy keeps (1) and (2) in check but when this doesn’t keep pace, the cells die

If this hypothesis is correct, then there could be at least three distinct causes of Parkinson’s, which in turn would mean different treatments for different people:

(1) An environmental or genetic factor causes more alpha-synuclein than normal to go rogue.

(2) An environmental or genetic factor causes more mitochondria than normal to malfunction

(3) The normal autophagy process is inhibited in some way

Genetic factors in Parkinson’s are a very active area of research and I am currently awaiting results from my own genetic testing. In the case of (1), the SNCA gene that encodes for alpha-synuclein has alleles that are associated with increased risk of Parkinson’s. In the case of (2), mutations in the genes PINK1, PRKN, and others are associated with mitochondrial dysfunction and a similarly increased risk of developing the disease.

From an environmental perspective, pesticides are thought to increase the risk of developing Parkinson’s whereas exercise, smoking and caffeine consumption are all correlated with a decreased risk. It is also possible there is a link with diabetes. And recent theories propose that Parkinson’s starts in the gut and spreads to the brain. But the underlying mechanisms behind these associations are far from understood.

Factor (3), autophagy, is interesting. It is thought that there is a strong link between the natural process of ageing and a slow-down in autophagy (a long topic of discussion in its own right, see paper here for further information). So in a sense, Parkinson’s could actually be a normal feature of ageing: maybe, like grey hair and wrinkles, we would all get it at some point if we lived long enough. And, like grey hair, a few of us get it earlier than we would expect.

Autophagy is thought to be boosted by a restricted calorific intake - meaning that starving yourself (within reason) may actually extend life expectancy. Maybe this is the reason things like smoking reduce the risk of Parkinson's; because they suppress appetite and/or burn more calories, which in turn encourages autophagy, which clears away the rogue proteins. But this is just my own speculation.

Regardless of whether my views are correct or not, the upshot is that the cells in the substantia nigra gradually die and there is not enough dopamine to go around, leading to movement problems and other issues. Later on, the Lewy bodies can start affecting other areas of the brain too.

There is a further very basic – and also unresolved – question here: can new brain cells grow to replace the dead ones? In other words, are we born with all of our brain cells or can new ones (like other cells in the body) be generated in our lifetimes? The scientific community is divided on this subject too. See, for example, a recent article in the Economist here. Obviously, if replacement cells could be encouraged to be generated, we would have a meaningful treatment.

There is so much research and yet the fundamental biological mechanisms underpinning Parkinson’s are not properly understood. All of which means that a genuine cure (i.e. something that actually reverses the progression of the disease) is still, in my humble and no doubt under-informed opinion, some distance away. Nevertheless, there are many promising trials underway for treatments that can at least manage the symptoms or slow down the inexorable death of the dopaminergic cells.

And so, I wait for news. Both that a basic understanding of (my personal version of) Parkinson’s may transpire, and that further treatment options may be developed.

In the meantime, I have ordered a new mobile phone to replace the one with the dead battery. When the new device arrives, I will be able to easily transfer my old data across.

In contrast, the brain that I was born with is, for better or worse, the one I get to keep for a lifetime.