Neurodegenerative Diseases — Kevin Talbot / Serious Science
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Neurodegenerative Diseases — Kevin Talbot / Serious Science

It’s quite difficult to tell where the word
neurodegeneration came from. It’s now an accepted concept but I think as
in all areas of science it’s very important to remember that this is a word that has been
coined and we need to be very cautious before we think we’ve understood something just by
naming it. What we mean by neurodegeneration is that
the nervous system evolves and develops normally in an individual, and at some point in their
life it begins to fail in a series of rather characteristic ways. There are some commonalities between these
different neurodegenerative diseases, but actually, one very important principle is
that they are all rather separate entities. That’s important from the point of view of
trying to understand the biology and also how we might provide therapy for these disorders. A lot has been written in the past about the
overlaps and some of the things that might mean that there might be one treatment for
different forms of age-related degeneration but actually the more we learn the more we
realize that these are complex diseases with their own particular biology. So the chief neurodegenerative diseases in
terms of the way they affect society is Alzheimer’s disease, it’s clearly the most important. So Alzheimer’s disease overwhelmingly is the
public health problem that we need to try and solve. Alzheimer’s disease was characterized in the
late 19th century by pathologists, by people looking down microscopes and saying: well,
here’s somebody in life who has a failing nervous system, what do we see in the brain? What characteristically was observed is a
particular way in which proteins are accumulating in the brain: in Alzheimer’s they are so-called
amyloid plaques and tau tangles. In other diseases like Parkinson’s there are
particular forms of protein hallmark, in Parkinson’s it’s called the Lewy body and in ALS it’s
called the ubiquitylated inclusion. So in common there is the observation that
protein is accumulating in these cells but these are different proteins and actually,
we don’t know whether it’s the accumulation of protein which is an injury phenomenon,
or that’s a protective response, or it’s simply an epiphenomenon. So neurodegenerative diseases have the clear
common feature that they are age dependent: we don’t see these disorders in infants or
children except in very specific genetic disorders where the brain suddenly degenerates, but
again, in rather different ways to the way in which it does in aging. So, an important question which often gets
discussed is whether normal aging and neurodegeneration are in fact the same thing. That’s a very complex topic. Again, what do we mean by aging? We’re seeing the passage of time and things
getting older. Is there a process called ‘aging’? So at the cellular level, there is a concept
of cellular senescence where a number of things happen that prevent the cell after a particular
period of years from regenerating and that’s effectively why aging occurs. The processes which are carrying neurodegeneration
are somewhat different, however, they intersect because despite having a genetic makeup which
might promote neurodegeneration either in the single gene level or in a complex way
until you get aging, these other cofactors do not trigger the disease. So we have to understand both of these things
and how they intersect. We are really at the beginning of our understanding
of that. So the classic degenerative disorders of Alzheimer’s
and Parkinson’s and ALS account for most cases but then there is a whole range of other disorders
which we classify under neurodegeneration. When people have sought to try and derive
a taxonomy for neurodegeneration they have often put things together. For example, disorders that look a bit like
Parkinson’s disease such as progressive supranuclear palsy, multiple system atrophy, corticobasal
degeneration, Lewy body dementia, these disorders have some features of Parkinson’s, so they
are called parkinsonian or parkinsonism disorders. Yet, while under the microscope there are
some features which they have in common. There are clearly some differences. So, even though progressive supranuclear palsy
gets misdiagnosed as Parkinson’s disease under the microscope is a taupathy. The key protein which is deposited is tau
protein, more like in Alzheimer’s desease. Corticobasal degeneration is the same whereas
multiple system atrophy is what’s called a synucleinopathy because the protein in Lewy
bodies in Parkinson’s is alpha synuclein that is also present in multiple system atrophy. So you begin to draw a family tree of these
diseases based on the proteins accumulating but actually again one can be rather misled
by that. Parkinson’s disease has numerous genetic contributions
some of which are very well understood. With disorder like multiple system atrophy
despite being a synucleinopathy there are not really any convincing examples of familial
inheritance or genetics except in very rare situations. So we are still struggling to understand how
we might organize these disorders into a system. If you just simply do it and you rely on neuropathology
you get one answer, genetics – another answer, clinical features – another answer. So clearly what you really have to do is to
become rather ultra reductionist and really understand the disorder at the more molecular
level. There’re new technologies such as transcriptomics
and proteomics are beginning to redefine diseases into subtypes based more on the biological
profile and signals that are present in patient biofluids, for example. However, with the great Public Health problem
that is Alzheimer’s disease, one of the big challenges is that the number of actual cases
of Alzheimer’s disease which are due to a single gene mutation is a very small indeed. In fact, ALS is much more of a genetic disorder
than Alzheimer’s disease. But for all of these conditions, the way into
therapy is through understanding the disorder, through modelling it in vitro and in vivo
using the genetic forms of the disease. There are currently no real ways of doing
it. Modelling sporadic disease is very challenging. Typically in the laboratories, we take a genetic
mutation: let’s choose an example of C9orf72, that is a gene which can cause ALS, it can
cause frontotemporal dementia both of which pathologically look rather similar under the
microscope with ubiquitylated inclusions. Clinically they are slightly different. They can occur in the same family, so there’re
some overlaps but they’re quite different phenotypes. So we might typically seek to model these
diseases by using induced pluripotent stem cells to then establish in a culture of motor
neurons or cortical neurons and try to understand the transcriptomic profile which is triggered
by the mutation. But when you have a specific genetic mutation
– and C9orf72 accounts for significant numbers of patients: 40% in our population of the
familial cases of ALS and up to 10% of all ALS cases are due to mutations in C9orf72. So it’s a very important target. The kind of therapeutic approaches that you
might apply here includes antisense oligonucleotides. The first clinical trials of antisense oligonucleotides
are now in development. The way that C9orf72 causes disease is because
of an expansion of an intronic region of repetitive DNA which then gets massively expanded from
a handful of repeats of a hexon nucleotide into about a 1000-1500 repeats to cause disease. So antisense oligonucleotides can be used
to antagonize the RNA which is the product of this and therefore in the laboratory you
can demonstrate that you can correct the cellular phenotypes. Whether that is gonna be possible in the intact
human nervous system once the disease has been triggered we are going to learn in the
next few years. But obviously one of the key therapeutic developments
that we are very excited about is the concept of genome editing. In my laboratory and many others around the
world, we’ve simply used CRISPR/Cas9 genome editing to remove the mutation in C9orf72
and correct everything in the cells and that at least establishes that concept, the principle
that if you could apply that to patients you could actually correct the genetic mutation. The logical consequence of that is that what
you’d really like to do is to correct it before the disease begins. For most degenerative diseases of the nervous
system there’s very good evidence that when the patient presents to a clinician they have
already had the disease for a number of years and that they have used up most of their intrinsic
reserves. For Alzheimer’s disease when it’s been studied
the familial types there is already evidence of misfolded protein, the accumulation of
beta amyloid for 20 years or more before memory becomes disturbed. That tells you that there is an enormous amount
of reserve. So what we’d really like to do is to treat
people 20 years before they’re likely to develop memory problems. To do that you need to be able to detect them,
you need to be able to treat them safely so that you do not cause any harm, and need to
work out how to do economically since these kind of treatments are in therapy very expensive. So there are huge challenges even with the
apparently rather simple genetic forms of neurodegenerative disease. If you consider that most forms are not clearly
in a simple way genetic, they are sporadic where there are multiple different genetic
susceptibilities, environmental triggers, intrinsic factors within the nervous system
then we really have a huge challenge. I think to really conclusively treat neurodegeneration
is a very complex task which is going to involve preventive strategies and it’s going to involve
corrective strategies which really raises the question of whether regenerative medicine
is possible in these disorders. Around the world numerous institutes of regenerative
neurology have been established. The concept is to try and reconstitute those
nervous connections in order to restore function. That is a huge challenge. If you take the number of neurons there are
in the brain which is likely to be twenty billion or so, each of those on average has
reciprocal connections with maybe thousands of other cells. So the architecture of the brain which allows
us to think, allows us to move and feel and do all our other functions is immensely complicated
and arises during embryological development through an orderly expression of hundreds
of genes which are patterned, signaling molecules, migration of cells and establishing of synaptic
connections. Of course, we have spent a hundred years or
more looking down a microscope at these inclusions in degenerative diseases. The real physiology of these disorders or
pathophysiology is of the synapse which is very far away from the cell body, difficult
to visualize. It’s synaptic function which gets lost in
Alzheimer’s, Parkinson’s and ALS and that is what needs to be protected. So overall the challenge here is very huge
but it’s a technical challenge and therefore ultimately will be overcome through improved
knowledge but one can not underestimate it.

One thought on “Neurodegenerative Diseases — Kevin Talbot / Serious Science

  1. I'm very much an ignoramus, but over the past 100 yrs our eating habits have been swayed to eat veg oil ( engine fuel) and overly processed carbs. What if the myelin sheath prefers Saturated fats and too much sugar/ carb consumption is interfering with synapses? (Predestined genetic disorders apart). This explosion of brain disorders has to have a common denominator somehow. Thanks for this interesting interview.

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