When proteins misfold, it can have severe consequences for the nervous system. There are three main reasons for this. First, loss of function can occur if not enough of a particular protein properly folds, leading to shortages. Second, misfolded proteins can form toxic aggregates that disrupt neuronal activity and cause cell death, as seen in Alzheimer's disease. Third, prions are misfolded proteins that can convert normal proteins into more misfolded ones, spreading throughout the nervous system and causing neurodegeneration. The complex nature of the nervous system means that each component, including the many proteins involved, must work properly or neurological disorders can result.

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When protein-folding goes wrong: why
does it matter so much to the nervous
system?
The word ‘protein’ derives from ‘prota’, the ancient Greek term meaning, ‘of
primary importance’.1 This speaks for itself;proteins are, indeed, of prime
importance. Over 100,000 sui generis forms of proteins reside within an archetypal
human cell,2 with each and every structure coded differently and exactly right to be
able to implement its individual function. However, human proteins consist of solely
20 kinds of amino acids.3 How is it possible for this astonishing breadth of diversity to
be achieved with such a minimal number of building blocks? The answer lies in its
shape - proteins can fold. In fact, an incipient (‘nascent’) amino acid chain is
biotically rather ineffectual. This primary structure that resembles a lengthy pearl
necklace must fold into a defined three-dimensional shape in order to become a
working protein.1 The wealth of possible configurations they can come in is
astronomically vast, there being an approximate nonillion (1030) feasible states, out of
which only one viable arrangement exists; ergo it is not surprising that folding can go
wrong. More and more neurodegenerative disorders such as Huntington’s chorea,
Creutzfeldt-Jakob disease (the human equivalent of mad cow disease), Parkinson’s
disease, motor neurone disease (MND) or amyotrophic lateral sclerosis (ALS), made
globally known by Stephen Hawking, and the common Alzheimer’s dementia have
begun to be acknowledged as the end products of faulty protein folding in the brain
and in the remaining regions of the central nervous system.4
The immense importance of protein folding is evident; so why does it fail? The
predominant issue is the great congestion of the cellular environment.2 When proteins
fold, they automatically collapse into a globular structure due to the process being
thermodynamically directed by the hydrophobic effect3 - the hydrophilic amino acids
remain at the surface while the hydrophobic amino acids shy away from the water,
forming a water-hating core. The problem is that the hydrophobic amino acids are
‘sticky’, therefore when proteins are in the mid-folding stage they can cluster en
masse to form obstinate aggregates.2 In teeming milieux reaching concentrations of
400 gram per litre,2 how are proteins even able to fold at all without tangling into
intractable mounds of debris? In the mid-20th century, Christian Anfinsen
demonstrated that proteins fold completely of their own accord using the data
contained within the amino acid sequence.3 This remains true, but in the later years of
the same century, helper proteins, aptly named ‘molecular chaperones’, were

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discovered to fill in the gaps as to how folding can take place in the cramped locality
of cells. These chaperones inhibit aggregation by covering the adhesive hydrophobic
surfaces of incomplete proteins.1 2 3 ‘Chaperonins’, a type of molecular chaperone,
operates by encapsulating in a cylindrical enclosure an unfolded protein, enabling it to
fold in seclusion, before freeing the lid to disengage the finished product and moving
on to give succour to another.2 3 As a means of protein degradation to jettison proteins
that are mis-folded beyond repair, ‘proteasomes', themselves proteins, demolish and
sever them into their basic building blocks for future protein synthesis through
proteolysis1 2 - this not only recycles resources but also creates space to curtail
aggregation. Nevertheless, despite all of this multifarious biological technology that is
protein quality control, protein folding still fails. One factor is the possession of a
mutative gene that affects an amino acid. There may be a transmutation in the primary
structure, whether it be a substitution, inversion, insertion or deletion of an amino acid
in the chain, rendering the normal ‘native’ fold of the particular protein to be
unachievable and thus unable to execute its precise task.1 A well-known instance of
this is the hereditary condition cystic fibrosis, which is primarily engendered by a
deletion of one amino acid in the carrier protein for chloride ions called the cystic
fibrosis transmembrane conductance regulator (CFTR). This protein transports
chloride ions across membranes of cells that produce mucus, sweat, saliva, tears, and
digestive enzymes; with cystic fibrosis there is not enough of the protein, resulting in
abnormally thick mucus that leads on to many other problems.1 2 3 Another root of
error has a broader effect on many proteins rather than a specific one. It has been
suggested that ribosomes make mistakes in as many as 1 in 7 proteins during
translation1 - these errors may just as well be harmless as they can be deleterious if the
altered shape of the protein turns out to give detrimental effects in a ‘Jekyll and Hyde
Effect’.6 Even if an amino acid has no mutations or faults, cellular conditions such as
pH and temperature contribute to lowering the success rate of protein folding.1 In the
early 1980’s it was found that partially folded proteins are especially sensitive to
temperature and quickly clump together with heat, hindering successful folding from
occurring under divergent conditions from which the organism is accustomed to.3
Alternatively, interference with chaperones and proteasomes will tamper with the
protein quality control system, leading to aggregation. Contemporary analysis of the
worm Caenorhabditis elegans indicates that these contrivances diminish piecemeal in
capacity;3 i.e. our anatomy slowly loses the ability to prevent aggregation and to clear
valueless proteins with old age, resulting in senile proteopathies such as Alzheimer’s.
Taking the fact that the very essence of our existence is our brain, it is logical
that proteins play requisite roles in it - in our nervous system. The nervous system is
an exceptionally intricate nexus of neurones that carries information as electrical and
chemical impulses. An electrical signal, known as an action potential, sweeps along an

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axon until it reaches the synapse, the meeting point of neurones that must be spanned
chemically.9 Every plasma membrane has a protein labelled the sodium-potassium
pump, fittingly termed after its job of actively transporting three sodium ions out of
the cell for every two potassium ions brought in.7 Since K+ can easily diffuse outside
of the cell down their concentration gradient while Na+ cannot enter effortlessly to
replace the lost charges, a resting potential is maintained across the membrane; the
extracellular space always has a slightly more positive charge than the intracellular
space, the potential difference in charge being about -70mV.7 9 An action potential is
initiated when the neurone is depolarised - in other words when there is a large
reduction in the value of potential difference, namely to -40mV.9 When the potential
difference becomes less negative than this, protein channels that are responsive to
voltage, appropriately entitled voltage-gated channels, open. There is an immense
inflow of Na+ through ajar sodium voltage-sensitive gates down the electrochemical
gradient - a combined outcome of both the concentration gradient, where there are less
intracellular Na+ than extracellular, and the electrical potential gradient, where the
charge inside the cell is negative compared to the outside.7 This tremendous influx of
Na+ induces the potential difference athwart the membrane to change from -40mV to
+40mV,9 at which point the sodium voltage-sensitive gates close and potassium
voltage-sensitive gates open in turn to restore the resting potential and terminate the
action potential in that precise position in the neurone.7 Notwithstanding, the electric
impulse continues to gain impetus. The inundation of Na+ are attracted to the less
positive surroundings on either side of the region of depolarisation. This compels the
ions to move sideways and depolarise the adjacent area, triggering the sodium
voltage-sensitive gates to open and so forth until the action potential reaches the cell
surface membrane of the presynaptic neurone. Electrical impulses are unable to
traverse the synaptic cleft, the interstice between neurones; hence, as previously
mentioned, the message is transferred as a chemical impulse. Calcium ion channels,
proteins distinct to Ca+ and sensitive to the change in potential difference, open. Ca+
flood into the synaptic terminal and prompt synaptic vesicles containing
neurotransmitters, chemicals produced in neurones that relay information to another
cell, to fuse with the presynaptic membrane for exocytosis to ensue.8 The
neurotransmitter acetylcholine (ACh) is the most abundant in our body and critical in
cognition, and accordingly will be used to exemplify the activities in a (cholinergic)
neurone.12 ACh molecules diffuse across the cleft, interlock with ACh receptor sites
on ligand-gated ion channels - proteins which then unlock to allow Na+ through - in
the postsynaptic membrane and provokes the incursion of Na+ into the neighbouring
neurone, possibly setting off an action potential as the cell is depolarised.8 To revert
our focus to the topic at hand, the motive for the antecedent explanation is to illustrate
the modus operandi of the nervous system, as well as its intricacy that necessitates

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each constituent to work properly lest it malfunction. This, along with cognisance of
protein folding, lays the foundation for understanding the bona fide enigma: when
protein-folding goes wrong, why does it matter so much to the nervous system?
The cerebral troubles that arise from mis-folded proteins are threefold: the first,
rather straight-forward reason is dubbed the ‘loss of function’2. This transpires when
not enough of a particular protein folds properly, inducing a shortage of proteins that
can fulfil a peculiar purpose. Loss of function is one origin of the aforementioned
proteopathies cystic fibrosis and ALS;2 in the latter, insufficient angiogenin proteins
are synthesised, culminating in scant specialised ‘workers’ to stimulate angiogenesis
(the formation of blood vessels) in order to purvey motor neurones with oxygen and
nutrients.10 The second acute repercussion is that some mis-folded proteins are toxic
to cells when they clump together to form insoluble aggregates.2 3 These clusters
disrupt neuronal activity and bring about cell death. Alzheimer’s disease (AD) is a
prime example of a malady precipitated by aggregate toxicity. The mis-folding and
aggregation of two proteins, amyloid beta (Aβ) and tau, is what characterises this
illness and what has been hypothesised to be its cause. Aβ is a soluble protein
fragment that is always present (although its use is yet to be determined) in the
extracellular space around neurones in the brain, derived after cleavage by beta and
gamma secretase of the amyloid precursor protein (APP) - a transmembrane protein
concentrated in synapses that is critical to synaptic growth and repair.11 12 13 In AD, Aβ
accumulate to form soluble, synaptotoxic oligomers as well as insoluble beta-pleated
amyloid fibrils that are the main constituent of senile plaques. These atypical
extracellular senile plaques deposit outside and around neurones in dense clumps,
obstructing the correspondence within neurones in the central nervous system and
precipitating neuronal death selectively in the entorhinal cortex and the hippocampus
involved in memory.11 12 Tau is a protein customarily used to maintain the structure of
a neurone by stabilising microtubules, tubes used to transpose nutrients to the axon
and dendrites, but when it becomes mis-folded, it accumulates inside neurones to form
neurofibrillary tangles. The microtubules fall apart due to lack of useable tau holding
them together; in addition, the intracellular neurofibrillary tangles impede axonal
transport, thus these two factors combined inhibits the neurone from receiving the
enzymes and nutrients it requires and evokes cell death.11 12 13 Neurodegeneration in
the cortex and hippocampus begets the profound memory loss that typifies AD.
Thirdly, one type of mis-folded protein deserves special attention: the ‘prion’. Stanley
Prusiner coined this term in 1982, short for ‘proteinaceous infectious particle’,14 after
its ability to corrupt other serviceable proteins to its twisted state and thereby
spreading the ailment like a virus. The prion was discovered by Prusiner (awarding
him his 1997 Nobel Prize in Medicine) as the fruition of his analysis of scrapie, an
affliction for sheep,14 15 and was also ascertained to be the causative agent for a class

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of infirmities - therein including mad cow disease, kuru and Creutzfeldt-Jakob disease
(CJD) - which are distinguished by their slowly-evolving symptoms and
neurodegeneration so dire that myriad apertures appear where grey matter is depleted
to leave the brain resembling a sponge.14 Creutzfeldt-Jakob disease is the most
prevalent prion disease (Transmissible Spongiform Encephalopathy or TSE) in
humans; but even then it is rare, affecting only one in every million people.16 It is
effectuated when a typical prion protein - which is found throughout the body and
although not essential, does seem to aid neurones in communication and ferrying of
minerals - folds abnormally into a flat sheet structure rather than the expected helical
one.17 This unwonted prion infects standard prions by producing a small polymer, no
more than perhaps 28 molecules, of mis-folded prions called a ‘seed’.15 As more and
more prions are converted they aggregate inside neurones, disrupting its functioning
and killing the cell; once the neurone dies and shrivels, the prions leak into the healthy
surrounding tissue and continue to transfuse deviant protein folding without any
reaction from the immune system. Currently CJD is rapidly and invariably fatal with
90% of victims dying within a year of contraction.16 Symptoms commence with
impaired memory and progress to spasmodic jerking of the muscles (myoclonus)15
and blindness16 until the patient ultimately becomes comatose and dies. Consequently,
the best that can be done for the patient is to alleviate the symptoms in order to make
the individual as comfortable as possible.
To recapitulate, proteins are paramount; every minute transaction in our body
relies on their faultless performance. Ergo when they are fabricated erroneously,
whether this failed folding be ascribable to genetic mutations in the DNA, ribosomal
errors or chaperonal operation being hampered, the body suffers catastrophic
repercussions. As we have gained an introductory perception of the delicate, byzantine
machine that is our nervous system, we can also see that each cog in the wheel is
crucial in order for our brain to work normally - for us to still have that mainspring of
life makes us ourselves. This can be lost through ‘loss of function’ - the genesis of
ALS - as well as through aggregate toxicity that can result in disorders such as
Alzheimer’s disease and lastly, through the creation of noxious, mis-folded prions to
bring about Creutzfeldt-Jakob disease and other Transmissible Spongiform
Encephalopathies. The grave consequences on our nervous system caused by protein
mis-folding is such a spontaneous and unpredictable mistake, making it such a
problematic issue to tackle. One can only look to research in the future - after all,
medicine can only advance.
Bibliography:
1. Chauhan, A.K. (2009). A Textbook of Molecular Biotechnology. New Delhi. I.K. International
Publishing House Pvt. Ltd.

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2. Geiler, K. (2010). Protein Folding: The Good, the Bad, and the Ugly. Science in the News,
Harvard University. Issue 65. Available from: http://sitn.hms.harvard.edu/flash/2010/issue65/
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https://sites.tufts.edu/als/the-answer/angiongenin/
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National Institute on Aging. Bethesda, Maryland (USA). Available from:
https://www.nia.nih.gov/alzheimers/publication/2011-2012-alzheimers-disease-progress-
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(USA). Available from: http://neuropathology-web.org/chapter9/chapter9bAD.html
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disease-video
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neurodegenerative-diseases
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Encephalopathies). Rootstown Township, Ohio (USA). Available from: http://neuropathology-
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Bethesda, Maryland (USA). Available from:
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