Saturday 5 November 2022
I’ve
done my MSc in neuroscience, I’ve lived with Parkinson’s for six years and
counting, and I’m plugged into the research community, so now seems like a good
time to give my opinion on what is going on in the brain with Parkinson’s and our
best bet for a breakthrough in treatment.
Over 200 years since
English doctor James Parkinson published an essay about the eponymous disease,
and despite billions of dollars spent on research since then, the truth is that
we don’t understand what actually causes it, how exactly it progresses through
the brain, how to cure it, or even how to slow it down. The best we can do is
prescribe drugs that treat some of the symptoms.
However, we can
speculate what the big picture might look like from the various pieces of the
jigsaw that we can see. What follows is my personal best guess based on
everything I have studied. In summary, my view is:
- Parkinson’s is probably to do with the spread of misfolded alpha-synuclein
- There are multiple triggers but broadly one underlying disease
process
- The brain has natural defences against rogue proteins
- There are lots of other things going on in the brain and body that
affect progression of the disease
- Effective therapies are most likely to come from cell replacement and
boosting the brain’s natural defences
Let’s explore each of
these statements in turn, bearing in mind that everything I am about to say
could be completely wrong…
- Parkinson’s is probably to do with the spread of misfolding alpha-synuclein
When the brain of a
deceased person with Parkinson’s is examined under a microscope, it shows abnormal
clumps of a protein called alpha-synuclein. These clumps are called Lewy bodies.
It is not understood
exactly how and why these form, or how they spread, and it could be the case
that they are actually a by-product of something else going on. But a plausible
explanation is that they cause damage to neurons and spread by a so-called
“prion like” process. This term comes from “mad cow disease” where a protein
called a prion, which has misfolded, comes into contact with normal prion and
causes the normal prion to also misfold. Thus the defective proteins spread
slowly as individual molecules come into contact with one another.
The normal function of
alpha-synuclein is not well understood but it likely has something to do with
regulating synaptic vesicles. Vesicles are containers within a cell, in this
case containers of neurotransmitters like dopamine that are used to send
signals between neurons. The gene that encodes alpha-synuclein is called SNCA
and, indeed, rare mutations of SNCA can cause Parkinson’s at a relatively early
age. So the hypothesis is that alpha-synuclein which normally facilitates
communication between neurons can go rogue, and this perhaps both reduces the
availability of neurotransmitters and also somehow damages neurons.
- There are multiple triggers but broadly one underlying disease
process
Parkinson’s is highly
variable across individuals, both in terms of its symptoms and its progression.
In medical terminology, it’s heterogenous. It’s tempting, therefore, to
think there may be several subtypes and this is what I did my MSc thesis on.
“Subtyping and predicting the progression of Parkinson’s disease using machine
learning” was the title and I was pleased to get a mark of 78% for it. But the
conclusion I came to after analysing a lot of data was that it is more likely
that there is a single underlying disease (with the possible exception of some
rare genetic forms which need not concern us here) but with lots of factors
that influence how it manifests itself, a topic which I’ll return to shortly.
There is a popular
theory called Braak Staging (named after the German neuroanatomist who proposed
it in 2003), which I think is probably right. This states that Parkinson’s
spreads in six stages through different regions of the brain as shown below. As
an aside, there is a similar version of this theory for Alzheimer’s.
Braak goes on to
hypothesise that Parkinson’s can start either in the nose, in which case it
gets into the brain via the olfactory system, or the gut in which case it
travels up a nerve into the brain. This would seem to chime with clinical
evidence, namely that exposure to certain pesticides and industrial chemicals
can increase the risk of Parkinson’s, but that the early stages of Parkinson’s
are also associated with things like constipation. A number of people have
proposed that the underlying cause is a virus, but I think it is more likely
that it is the body’s own machinery that is at fault, not the work of a
pathogen.
- The brain has natural defences against rogue proteins
Nature has evolved all
sorts of defence mechanisms, like the immune system that fights off viruses and
bacteria, and many housekeeping processes that constantly clear away unwanted
proteins and other waste. Within cells there are structures called lysosomes
and proteasomes and processes like autophagy and ubiquitination, all of which
clean up and recycle mess in the cell. And in the human brain, there are just
as many glial cells as neurons which perform a variety of support functions including
cell repairs and removal of toxins.
I would hypothesise
that rogue proteins like the misfolding alpha-synuclein may actually be quite a
common occurrence but they are kept in check by these many different systems.
When these natural housekeeping processes are compromised then Parkinson’s
becomes more likely. For example, variants of a gene called GBA increase the
risk of Parkinson’s and GBA has a role in lysosomes mentioned above. Similarly,
the genes LRRK2 and parkin have roles in autophagy and ubiquitination, and
variants of these also increase the risk of developing Parkinson’s.
- There are lots of other things going on in the brain and body that
affect progression of the disease
As well as genetics
there are several other factors known to affect the risk of developing
Parkinson’s. You’re more likely to get it if you’re male but less likely to get
it if you’re a regular smoker. Caffeine consumption may play a role and there
are possible links to things like diabetes. What is going on here?
Biological systems are
not simple. They have not been designed (by some deity or otherwise); rather
they have evolved over millions of years in complicated and unpredictable ways
with all sorts of checks and balances and compensating sub-systems. They work
because they have evolved to work, not because there is a sensible blueprint of
how they should operate. The brain is particularly complex in this respect.
I think what is
happening is that neurons, which consume lots of energy and are awash with
chemical messengers, are in a constant battle to clear away toxins, and to keep
inflammation under control when cells get damaged or energy-producing
mitochondria burn out. Perhaps the rogue proteins also cause inflammation. This
ability to keep cleaning up and to keep inflammation under control, probably
degrades with age. A few rogue proteins get seen off in the normal course of
business, but a sustained onslaught of dodgy alpha-synuclein tips the balance.
This slowly spreads across a lot of the brain but the dopaminergic cells in the
substantia nigra are few in number and particularly delicate, so they die
easily and the result is a lack of dopamine that in turn leads to the motor
symptoms of the disease. These are the first thing we notice, but the brain
started to lose the battle many years previously.
Presumably oestrogen
and nicotine somehow work to the benefit of the neurons, perhaps operating as
anti-inflammatories
The disease spreads
across much of the brain but the brain is an adaptive organ and can, to some
extent, compensate. So, everyone has a slightly different set of symptoms
according to how their brain is wired. Some people can no longer smell, others still
have sensitive noses; some people tremor, others don’t, and so on.
- Effective therapies are most likely to come from cell replacement and
boosting the brain’s natural defences
If the above is even
half correct then halting or reversing Parkinson’s once diagnosed is going to
be difficult, and probably why essentially all drug trials to date have failed.
I do believe, however, that like vaccinating people for Covid, our best bet for
a disease-modifying therapy is to work with the brain’s natural defence
mechanisms. Exactly how we do this is not clear to me, and to be brutally
honest I am increasingly pessimistic that we will find disease-modifying therapies
any time soon. Perhaps the eventual answer will be a combination of drugs, for example
anti-inflammatories, anti-oxidants and drugs that boost processes like
autophagy and ubiquitination.
An alternative
approach, which is showing some success and now undergoing many clinical
trials, is to accept the progression of the disease but replace some of the
lost cells. If we can take a 60-year-old with Parkinson’s and give them some
fresh dopaminergic cells that will buy them another 20 years of being able to
move fluidly, then that’s a pretty good outcome.
With a couple of
exceptions (for example the hippocampus where short-term memories are stored),
the brain does not naturally replace lost neurons: once your brain cells die,
they’re gone forever. But we can grow some new ones in the lab from stem cells
and implant them. I wrote a bit about this in the last post and this approach
is not without its challenges. It’s expensive, it requires invasive brain
surgery and there are various technical issues like where to implant the cells.
It turns out that it’s better to implant them in the striatum where the dopamine
is actually used, rather than the substantia nigra, where the neurons would need
several years to grow axons that project into the striatum.
Experiments on cell
implantation were done as far back as the 1980s with some success. In those
days, embryonic stem cells were used, which have significant ethical issues
(you need six aborted embryos to treat one adult with Parkinson’s) but today we
have induced pluripotent stem cells which don’t have the same concerns though
are still complex to work with.
We shall see the results
of the current batch of clinical trials in cell replacement in the next 2-3 years. I think there is
a good chance that this will lead to a viable therapy a decade from now.
If this proves to be
the case, I’ll be one of the first in the queue.
