{"id":1712,"date":"2013-05-03T07:43:31","date_gmt":"2013-05-03T07:43:31","guid":{"rendered":"http:\/\/thetravellerslastjourney.com\/shai\/2018\/11\/27\/245-revision-v1\/"},"modified":"2019-07-14T02:47:13","modified_gmt":"2019-07-14T02:47:13","slug":"the-prion-protein-as-a-receptor-for-amyloid-beta","status":"publish","type":"post","link":"https:\/\/thetravellerslastjourney.com\/shai\/2013\/05\/03\/the-prion-protein-as-a-receptor-for-amyloid-beta\/","title":{"rendered":"The prion protein as a receptor for amyloid-beta"},"content":{"rendered":"

I’m currently – 03\/05\/13 – in the process of updating this. I’ve added the section “Update (May 2013)”, which is still a work in process (i.e. otherwise I would delete this note here).<\/small><\/p>\n

The title of this node comes from a\u00a0Nature<\/a><\/i>\u00a0communication in which recent research linking the\u00a0prion protein (PrP)<\/a>\u00a0and the\u00a0amyloid-beta (Abeta)<\/a>\u00a0protein was discussed. This is a new area of investigation which has seen some intense research in recent years. The obvious reason for this interest is that it suggests a link between different diseases: misfolded PrP is responsible for prion diseases, which include\u00a0CJD<\/a>\u00a0and\u00a0BSE<\/a>\u00a0(aka Mad Cows Disease), while aggregates of Abeta are very prominent in\u00a0Alzheimer’s disease<\/a>.<\/p>\n

Who is this for?<\/b><\/p>\n

Everyone<\/a>. But given that this is a fairly\u00a0specialized<\/a>\u00a0topic I have written this in sections of increasing technicality. For the non-specialist, I’d recommend reading the sections “Introduction” and “Lauren et al. (2009)”. You might find the section called “Continuing research” a bit unforgiving, so please feel comfortable then skipping to the final section. Even if you don’t have any science background please give the next few paragraphs a go, they were written for you. \ud83d\ude42<\/p>\n

Introduction:<\/h3>\n

Neurons and proteins<\/h4>\n

The human body is made up of\u00a0cells<\/a>\u00a0– something like 10 to 100 trillion cells. Each cell can be imagined as a small ball containing a copy of our DNA in 23 pairs of\u00a0chromosomes<\/a>. The\u00a0DNA<\/a>\u00a0sequence encodes for all the different\u00a0proteins<\/a>\u00a0the cells need in order to make a functional organism (like you). Our DNA encodes on the order of one hundred thousand unique protein forms, which all interact to form signalling cascades and modify their cellular environments.<\/a><\/p>\n

There are different types of cells. The reason they differ is that even though they all have the same DNA, they don’t read the DNA the same way. At certain points during development, cells are given fates – some cells are told to read their DNA one way and so become\u00a0neurons<\/a>\u00a0while others might read it another way and become muscle cells. Neurons are cells which are specialized to process and transmit information and form the major component of our brain and nervous systems, (the nervous system is what we call the information networks made of neurons).<\/p>\n

When a cell’s\u00a0fate<\/em>\u00a0(i.e. the way it reads its DNA) leads it to make a certain protein which is encoded in its DNA we say that that protein has been\u00a0expressed<\/em>. Among the myriad proteins\u00a0expressed<\/a>\u00a0by neurons are two that are of interest here: the prion protein (abbreviated\u00a0PrP<\/strong>) and the Amyloid-beta Precursor Protein (abbreviated\u00a0APP<\/strong>).<\/p>\n

PrP and the protein-only hypothesis<\/h4>\n

Research into PrP can be divided into two fields. One field is concerned with what the physiological function of PrP is, that is, why millions of years of evolution have produced and maintained the existence of this protein. The second field is concerned with PrP as the substrate of a group of related diseases known as prion diseases1<\/sup>.<\/p>\n

At the present time, there is strong evidence supporting roles for PrP in neuronal resilience to stress (e.g. following strokes), regulation of cell metabolism (i.e. energy usage and production), regulation of copper homoeostasis, immune cells’ responses, and more. If this list looks haphazard that is because in biology everything connects to everything2<\/sup>.<\/p>\n

The second question about PrP and disease stems from the protein-only hypothesis. This can be understood in the following way: there are many\u00a0protein misfolding diseases<\/a>. These are diseases that\u00a0involve<\/a>\u00a0a protein misfolding to form protein aggregates, and includes diseases like\u00a0Alzheimer’s disease<\/a>\u00a0and\u00a0Huntington’s disease<\/a>. Prion diseases also involve protein misfolding, but unlike those other diseases, the diseases\u00a0only<\/em>\u00a0require PrP. Whereas Alzheimer’s requires some sort of hereditary\u00a0mutation<\/a>\u00a0or toxic environment to manifest protein misfolding, in prion diseases all you need is a misfolded prion. In prion diseases misfolding prions (called PrPsc<\/sup>) interact with healthy PrP (called PrPc<\/sup>), teaching the healthy PrP to become misfolded too. That means that unlike diseases like Alzheimer’s, prion diseases can be spread by exposure of healthy PrP to misfolded PrP.<\/p>\n

APP processing and amyloid plaques<\/h4>\n

APP is another protein which is expressed significantly by neurons and has been a major interest due to the amyloid hypothesis in Alzheimer’s disease. Simply stated, the hypothesis suggests that the toxic plaques (protein aggregates) which form during Alzheimer’s disease form part of the disease mechanism (i.e. how the disease makes you sick). The way APP contributes to plaques is by being processed to form amyloid-beta (Abeta<\/strong>) – the protein itself gets cut to release a small protein called amyloid-beta which can aggregate.<\/p>\n

Now here’s a good question: so\u00a0APP processing into Abeta forms plaques, but why does this prominently affect neurons<\/strong>? Why is Alzheimer’s primarily a brain disease? Why doesn’t it cause muscle dystrophy or your skin to fall off? What I’m getting at is that perhaps if we know why Abeta affects neurons preferentially we could understand what the mechanism of Abeta toxicity is.<\/p>\n

Based on what we know from above, how could we answer this question? Above I talked about cells having different fates and expressing different proteins. If we knew\u00a0every single<\/em>\u00a0protein expressed by neurons, and then we put those proteins one by one into non-neuronal cells, then we could check which protein is responsible for Abeta’s affinity and toxicity to neurons.<\/p>\n

Lauren\u00a0et al.<\/em>\u00a0(2009)<\/h3>\n

In February 2009 a group published a paper in the prestigious science journal\u00a0Nature<\/em>. The paper was entitled “Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers” and was authored by Juha Lauren, David A. Gimbel, Haakon B. Nygaard, John W. Gilbert and Stephen M. Strittmatter.<\/p>\n

The set-up for this experiment is\u00a0incredible<\/a>\u00a0and is worth elaborating upon. The group accessed a neuronal\u00a0cDNA<\/a>\u00a0(complementary DNA) library. These cDNA are small pieces of DNA which separately correspond to every single protein expressed by neurons. They took all the 5000 cDNA’s from this library and expressed them in different combinations to form 225,000 clonal cell lines – this means they took different combinations of cDNA from the library and made a non-neuronal cell express it, then grew that cell up into large numbers. After making 225,000 separate cell lines, they treated the cells with a solution containing Abeta and measured which cell lines could grab onto the toxic Abeta. From all this, they came up with one strong candidate – PrP – and a number of weaker candidates (not considered here).<\/p>\n

So they’d identified PrP as binding toxic Abeta. What next? They continued their research by asking whether PrP was important for the actual toxicity observed with Abeta. They showed that toxic Abeta (i.e.\u00a0grouped<\/a>\u00a0Abeta) depends on PrP expression to kill cells, and that this occurs somehow by Abeta actually interacting with PrP, and that even Abeta’s ability to reduce neuronal signalling (i.e. the way different neurons send each other messages) is dependent on PrP. This was all extraordinarily impressive. So now what?<\/p>\n

Continuing research<\/h3>\n
\n

When Stephen Strittmatter discovered an unexpected link between key proteins in two devastating brain maladies \u2014 Alzheimer\u2019s disease and Creutzfeldt\u2013Jakob disease (CJD) \u2014 researchers in the field agreed that he was on to something big. But a year on, conflicting results, including findings published in Nature this month, have clouded that rosy picture and highlight the challenge faced by researchers seeking a way to arrest Alzheimer\u2019s disease progression.\u00a0<\/em><\/p>\n

“Key Alzheimer\u2019s finding questioned<\/strong>”\u00a0Nature<\/em>\u00a0(2010)<\/span><\/p><\/blockquote>\n

Since the original paper, a number of groups have pursued the question of PrP’s relationship to Abeta toxicity. Unfortunately, as indicated by the above quote, the picture has quickly become more complicated than the original results revealed. Here I intend to summarise the experiments described by those papers that have been published since Lauren’s 2009\u00a0Nature<\/em>\u00a0Paper. Please note that many of these are from leaders in the fields. The suggestions of contradicting results should\u00a0NOT<\/em>\u00a0be construed as indicating incompetency or fraudulence. Biology is the most complicated system we know, and these researchers are amongst the leaders in that field3<\/sup>.<\/p>\n