The amyloid proteins & their related diseases : An Introduction

clausewitz (60)in #bioengineering • 7 years ago

The amyloid proteins & their related diseases

Hello again curious readers!

Time has come to raise awareness on the Amyloid proteins and how they cause problems for cellular mechanisms and thereby human life.
Amyloid fibrils is made of miss folded or/and sometimes partially digested proteins. These fibrils cause widespread damage or form bigger plaques.
The different fibrils and plaques along with prions give rise to over 30 diseases such as: Ms, Parkinson's and Alzheimer's Disease . Protein plaques and their related diseases is affecting more and more people in the world.
In Usa alone, 5 Million citizens suffers from Alzheimer's disease and this costs around 200 billion each year in medical expenses and other care and I don´t think i will get any cheaper.

Amyloidosis have both genetic and physiological triggers, resulting in protein aggregation in different cells, or in the long run, amyloidosis as we call it.
These aggregates either put oxidative stress on cells causing wide spread cell damage or is excreted from the cell. Outside of the cell the aggregates then to build bigger plaques along with other aggregates and cause major damage to the affected organs.
Many different proteins is involved in causing plaque formation and this first post on the topic merely aims to give you an light overview.

After this introduction, i will write about the involved proteins in groups of a few or one and one, since a full review in one post would be a bit juicy here. Without further ado, here is:

Amyloid formation & involved proteins

The root cause of fibril formation is problems in protein folding. A freshly translated protein is a simple strain of amino acids. It´s different parts form different local conformations such as alpha helices or b-sheets. These structures then fold together into what is called the proteins tertiary structure, giving it an overall structure and if this fold is part of a bigger protein, it is also called a sub unit. The sub units form a quaternary structure of assembled sub units resulting in the complete protein and all of this process is extremely sensitive to mutations, even a single one.

Figure1 The folding process, after the tertiary structure is complete, two of these units are combines, forming the complete protein

Genetic mutations cause many of the known pathogenic progressions, by changing a single amino acid in a protein, it always tend to fold better or worse, in these cases worse. The miss folded proteins can start to aggregate, or as it´s called, form dimer s, which helps in e.g hiding hydrophobic parts. The dimers grow into amyloid oligomeres and then amyloid seeds. These are the building blocks of the amyloid fibrils, but also building blocks for filaments that directly fold into amyloid fibrils.

Formation process of the protein fibrils called Amyloid fibrils or when they get bigger, Amyloid plaques.

There many proteins known to be involved in amyloidosis and essentially any step of the folding procedure can go wrong. Only in the family of secretases, giving rise to alzhimers as age progresses, there are many different mutations that leads to alzheimers BUT fascinating enough also protective mutations! With this we already know how we could manipulate the genes to knock out gene specific alzheimer's, which we will go into in detail in the next post!

There are many other proposed cures for plaques as improved macrophage activity and my own favorite: Antibody conjugated proteases that folds at binding, it would be amazing to design this! There are many antibody treatments in phase 2-3 trails, hopefully some of them successes. These medicines will simply trigger the immune system to digest the plaques, hopefully rendering the leftovers harmless. The leftovers thou are in some cases the root of the problem, so the anti-body conjugated protease could improve the breakdown procedure and render the leftovers harmless.
Given the complexity of each protein and their extensive involvement in plaque formation, I´ve decided on the following order of presentation:

Posting schedule and involved proteins:

1: Beta-secretase I - Alzheimer's disease, Genetic background and curse.

2: Prion Proteins - Prion diseases such as Mad Cow disease, Infectious progression.

3: Immunoglobulines - Heavy chain amyloidosis & The Modeling and treatment of light chain amyloidosis.

4: Tau: Neurodegenerative diseases, taopathies, toxic tau & therapeutic ideas.

5: Cystatin C - Hereditary cystatin C amyloid angiopathy. Domain swapping and fibril formation. The mutant L68Q.

6: Gelsolin, The mutant D187N/Y, Familial amyloidosis if the finnish type. Cures: Furin, glycosaminoglycan and beta gelosolinase inhibition. Stabilize mutant as a cure ?

7: Human lysozyme: Lysozyme amyloidosis, many known mutants no cures!

8: Transthyretin(prealbumin): Senile Cardiac TTR amyloidosis. Men outnumber women 50:1.

9:High density lipoprotein: Related apolipoproteins: Serum amyloid A & apolipoprotein AI. Chronic inflammation resulting Serum amyloid A related amyloidosis

Since much of the work is done, except making everything comprehensible in a blog format, i will be releasing these posts every other day.

Here are some pictures i took of drosophila flies or rather tissue samples from drosophila slices after flash freezing them and/or parafin threating them, staining them with a standard procedure IHC staining and making slices by hand. Both flies carry the same mutation causing Alzheimer´s disease, but the later strain has also been modified to produce human lyzoymes.

n-syb-Gal4 females X Aβ42 males, Clear plaque formations can be seen.

n-syb-Gal4 females X Aβ42 + lysozyme males: I am no pathologist but this looks like slicing relices and some plaque, but much less so lysozyme is alzheimer´s preventive.

Higher quality examples of protein deposits, the top right picture corresponds to the same plaque as my pictures above.

Thanks for checking the post out, help raising awareness on amyloidosis and Alzheimer´s disease, sing up for clinical trails or just upvote & resteem :)

https://www.alz.org/research/clinical_trials/clinical_trials_alzheimers.asp
https://www.alz.org/research/you_can_help/participate_in_alzheimers_research.asp
https://www.gridcoin.us/

Happy 2018 Steemit!

#proteins #genetics #alzheimer #amyloidosis