Protein function and protein structure are directly linked.
Proteopathies refer to a wide range of diseases in which abnormalities in protein structures can cause protein misfolding, protein toxicity or abnormal configurations.
These diseases cause severe and fatal health problems for both humans and animals.
Below is a list with a few examples of proteopathic diseases.
The assignment requires you to select one of these diseases, and evaluate several criteria.
Human Prion Diseases
Sickle cell disease
Bovine Spongiform Encephalopathy, (BSE).
Chronic Wasting Disease, (CWD)
The body should include the remainder of the word count (900)
You should include the following information in your review:
A description of molecular events which cause your protein to change its normal state.
Discuss the causes of disease and current treatments.
c. Write a conclusion to your review that gives the reader a takeaway message about your review.
Alzheimer’s disease affects the most elderly over 65.
This neurodegenerative disorder has been a huge burden on the healthcare system worldwide, and it is predicted to increase in the next few years.
As it progresses clinically, the disease causes impairments in cognitive functions and loss of memory. (Dubois et al. 2016).
Disorders in adults are caused by abnormal misfoldings of amyeloid beta proteins (Ab) in the brain.
In Alzheimer’s patients, the prominent features of their brain tissues are neurofibrillary knots and intracerebral amyloid plaques.
These amyloid beta accumulations can lead to plaque formation. This affects the communication between the neuron cell or synapse.
These abnormal structures prevent neurons from communicating with each other, which can lead to impaired cell function. This could eventually result in death or dysfunction.
Some proteins can misfold abnormally, accumulating to form seeds. This is according to some reports.
Brain disorders such as protein misfolding have been linked to it.
Proteins are unregulated and self-assemble into aggregates. This is a tendency of major proteins. (Lyubchenko (2015). These altered protein structures act infectively as oligomers, amyloids, large numbers, and even amyloids.
These seeds and modified protein structures act as factors that can propagate themselves and trigger disease progression (Selkoe, Hardy, 2016,).
The oligomers in Ab 42 residues are thought to be the most toxic and soluble.
They attach to neuronal synapses and serve as infectious ligands.
These oligomers are responsible for Cytotoxicity, which is caused by the decline of neuronal synapses.
Economou and colleagues have shown that high-resolution atomic force microscopy can direct image Ab 42 protein dimers, hexamers, or dodecamers. These are seen as aggregations in earlier stages of Alzheimer’s (Economou et al. (2016)).
The preprotofibril could be as long as 100 nanometers in length and were single linked to dodecamer from Ab 42 layer.
Ab 40 residue was not found to contain hexamer. However, it was discovered that small oligomers were formed, which create branched chain-like networks and not separate structures. (Economou, Economou, et. al., 2016).
This suggests that the proteopathies found in Alzheimer’s and other cerebral diseases may be due to protein misfolding or corruption, eventually leading to neural synapse dysfunction.
The molecular mechanism has solved the mystery of Alzheimer’s pathophysiology.
There is evidence that Alzheimer’s neuropathological events have been displayed in a cascade in advanced order. This can be detected using dynamic biomarkers in-vivo.
The amyloid beta proteins can be found in many forms. They range from 37 to 49 amino acid by proteolysis.
This (APP), an inherent protein, is found in the neuronal synapses area and is also expressed in other tissues.
Its function is to maintain neuronal plasticity, regulate synapse establishment and export iron.
Ab-42 results from the action of b-g secretases in proteolysis of precursor APP. (Sakae et. al., 2016).
Figure (1) illustrates the process of amyloid-beta formation by proteolysis.
The activity of both proteases (b and g secretases) is facilitated by type 1 membrane protein, called b site-APP-cleaving enzyme (BACE 1).
Presenilin is the intramembrane component that facilitates g-secretase activity (Yuyama, Igarashi 2017).
Amyloid-beta42 has the highest tendency to accumulate in extracellular spaces around neuronal cells. This is why it has been linked to brain disorders such as Alzheimer’s and other neurological diseases (Lesne et.al., 2013 and Dohler et.al., 2014).
The amyloid stage is when proteins create elongated fibres that are not branched and have a backbone of stranded Beta sheets.
By exposing the backbone of amide and carbonyl groups (C=O) to proteins, they can become amyloid. These groups can form hydrogen bonds with different protein chains (Eisenberg und Jucker, 2012).
Few researchers believe that amyloid beta oligomers may link up with the plasma membrane-bound, cellular Pron protein (PrPC), and then eventually cause the degeneration in synapses.
But, amyloid b42 and PrPC complex binding provides a crucial understanding of the pathophysiology behind the degeneration of Alzheimer’s neural cells.
(Westaway and Jhamandas 2012; Um & Strittmatter 2013, 2013).
Also, PrPC flexibility was reported in studies. These studies revealed the binding site for PrPC to Ab to 23-27 residue sites and 95-110 residue sites (Dohler, Um, and Strittmatter, 2014).
PrPC is a neuronal glycoprotein and its function is not yet known.
Tau protein has the function of stabilizing microtubules during phosphorylation.
Tau protein becomes phosphorylated incorrectly and accumulates in fibrils. This can lead to thread formation in neuropil, soma, and tangles (CrespoBiel, 2012).
The threads create neurofibrillary twists (NFT).
This causes disruption of cognitive function and neural communication via synapses.
Reports have suggested that Tau proteins are responsible for synaptic plasticity, toxicity, and cognitive functions failure (CrespoBiel et. al., 2012).
This causes cognitive behavior to decline, as well as structure and function to be affected (Jack et. al., 2013).
As such, amyloid-beta proteins and tau proteins are both a contributing factor to Alzheimer’s structural and metabolic declination (Pascoal and al., 2017).
These amyloid plaques, which are outside the neuron cell’s cells, can be infected by seeding and intercellular transport as well as neighbouring neuron communication.
The aggregation and subsequent cellular stress can trigger immunity, causing cells to degrade and eventually resulting in cognitive and behavioural disabilities (Lyubchenko (2015)).
Older patients have difficulties remembering information and performing everyday activities.
The disorder of the brain is irreversible and progressive memory loss.
The accumulation amyloid-beta plaques occurs over a period of 15 year before the onset of symptoms (Yuyama, Igarashi 2017).
There has been a lot of research into therapeutic drug research for Alzheimer’s over the years. Unfortunately, there is currently no cure (Graham et. al., 2017).
There are currently four medications on the market, all in generic form. Prescriptions are based upon cognitive tests.
Three of these drugs have anticholinesterase properties and galantamine, and they act on the central nervous systems.
Memantine, which targets glutaminergic pathway and N-methyl D-aspartate(NMDA) receptor is FDA approved in the USA.
According to recent reports, excess glutamate at neuronal synapses is another pathophysiological mechanism that can lead to Alzheimer disease. It is also likely to be responsible for a lower uptake from microglia.
The clinical trial II for the postsynaptic Glutamate Inhibitor is still ongoing (Graham et al. 2017, 2017).
None of these drugs has been shown to be safe for long-term use, nor have they been shown to be effective in controlling the disease.
These drugs are used to slow the decline of cognitive behavioural functions. They are usually used in palliative treatment to provide symptomatic relief while improving quality life.
Alzheimer’s is an age-related disease. A lot of work and many different schemes have been done worldwide to uncover the pathophysiology.
However, Alzheimer’s has had less success because no specific drug has been developed that can alter the mechanism of action.
Alzheimer’s is a difficult disease. Although it is difficult to study the mechanism and identify biomarkers as well as design clinical trials, there is still hope for finding out what Alzheimer’s hallmarks are.
The pathology of Alzheimer’s disease is clearly revealed by amyloid-beta proteins and tau proteins. These proteins help to understand the process of plaque formation.
This is what motivates researchers to carry out extensive drug research and to create programs to defeat this chronic disease.
Crespo-Biel N., Theunis C., Van Leuven F. (2012).
International Journal of Alzheimer’s Disease. “Protein Tau is the prime cause of synaptic, and neuronal dysfunction in Alzheimer’s Disease.”
Article ID 251426.
Brain, 137: pp.
B. Dubois. A. Padovani. A. Scheltens. P. Scheltens. A. Rossi. G. Dell’Agnello.
“Timely Diagnosis of Alzheimer’s Disease: A Literature Review of Benefits & Challenges”, Journal of Alzheimer’s Disease. 49(3). pp.
N. J. Economou and Giammona M. J. Do. T. D. Zheng, X. Teplow, D. B. Buratto, S. K. Bowers, M. T. (2016).
Journal of the American Chemical Society, 38(6), pp.
Eisenberg, D., & Jucker, M. (2012).
Cell, 148(6). pp.
Graham, W. V. and Bonito-Oliva A.
A. Bennett, D. A., & Ashe, K. H. (2013).
Brain, 136(5). pp.
“Amyloid misfolding, aggregation. and the early onset disease of protein deposition disorders: insights from AFM experimental and computational analyses’ AIMS Molecular Science. 2(3). pp.
Pascoal T. A. Mathotaarachchi S. Mathotaarachchi S. Mathotaarachchi S. Mohades S. Benedet A. L. Chung C.O. Shin M…. and Rosa Neto P. (2017).
“Amyloid B and hyperphosphorylated Tau synergy drive metabolic decline in preclinical Alzheimer’s Disease” Molecular Psychiatry. 22(2). pp.
Sakae N. and Liu C.C., Shinohara M., Frisch Daiello J., Ma L. Yamazaki Y…. and Kanekiyo T. (2016).
‘ABCA7 Deficiency Accelerates Amyloid b Generation and Alzheimer’s Neuronal pathology’, The Journal of Neuroscience. 36(13), pp.
Selkoe D. J. and Hardy J.
EMBO Molecular Medicine, 8(6). pp.
Um, J. W., & Strittmatter S. M. (2013).
Prion, 7, pages.
Westaway (D.) and Jhamandas (J.H.
Prion, 6, pp.
Frontiers of Neuroscience, 11, pp.