Classification as Prion Disease
 

Doesn't it seem like every other month, depending on latest research that PD is a mitochondrial disease, then a channelopathy, and now latest is prion. It seems like there should be criteria for classifying diseases, so I have no idea how it's done. Maybe they haven't settled on just "one" for PD because there are so many different pathways to disease. It seems as if we all end up with mutant proteins then it should be prion. Anyway, I ran across this person's theory and he sees the main cause of PD as a fungal infection. I am not going to pass judgment on him; if you read the comments enough have done that. However, I was intrigued by his approach to classifying and seeking etiology. I tend to agree with his view of how modern science has bungled this for us.


MedKB (Medical Knowledge Base)

Blind men and elephants
 

I assume that everyone knows that story. All these researchers know a little corner of the critter and are convinced that they are beholding the entire animal. Everybody's right and nobody's wrong and the grants keep on coming.

what is PD?
 

Though it seems like PD story is changing every other month, it is actually coming together as a coherent story (IMHO of course!). This is my take on what PD is at the cellular level, mostly based on current literature and a few hypotheses that are yet to be tested. It is rather long and semi-scientific…………….

Connecting the dots 1: Gene mutations/modifications to PD
If you look at the genes/aberrations in gene products associated with PD, SNCA, Parkin, PINK1, DJ1 and UCHL-1 and LRRk-2 top the list. what do these genes do and how are they responsible for PD?

SNCA is alpha-synuclein, a small protein present in the neurons. In normal, healthy neurons, alpha-syn looks like a thin strand of thread and being thin and untangled are very critical for its function as a chaperone protein. Its job is to receive important guests (proteins) at the door (cell membrane) and take them to the right place at the right time (for example mitochondria, nucleus etc.,). Mutations in SNCA gene make alpha-syn sticky and this protein gets all tangled and unable to move and chaperone others.
Again in normal healthy neurons, if alpha-syn gets tangled and/or fails to do its job, it is immediately removed from the job. It will get tagged with another protein called ubiquitin and marks tangled alpha-syn as an inefficient or useless protein. This tagged protein is sent to a cell compartment called lysosome where it is degraded. This process called autophagy involves many proteins that work together (collectively known as ubiquitin-proteosome). PARKIN and UCHL-1 are part of this system and keep “bad” proteins from away.

Now imagine a scenario where mutations (inherited) and/or exposure to pesticides (environmental) make alpha-syn to become sticky and tangled. It can no longer chaperone other important proteins into the cell. Cell functions slow down and cells are distressed. It is time for the ubiquitin-proteosome to step in and eliminate tangled alpa-syn from the neuron. At this stage a neuron can encounter two problems:
One is if there are mutations in Parkin, UCHL proteins (as is the case in some PD patients) disrupting their function. The second hurdle is even if there are no mutations, tangled alpha-syn inhibits the normal ubiquitin-tagging system. Net result is the accumulation of toxic alpha-syn within the neuron.

Connecting the dots 2: Neuro inflammation in PD
Tangled up alpha-syn is toxic to neurons. Dead or dying neurons release tangled alpha-syn into the brain. Microglial cells take up tangled alpha-syn and get activated. They start to make pro inflammatory cytokines (TNF-alpha, IL-1, IL-6 etc.,) leading to neuro inflammation. Inflammatory cytokines attract immune cells to the brain. These immune cells perceive tangled alpha-syn as a pathogen-derived protein rather than a component of the body and work hard to get rid of it. During that process, they produce cytokines and neuro inflammation continues.

Connecting the dots 3: PD and auto immunity
Tangled alpha-syn and/or fragments generated from it get into the blood stream and circulate in the body. The immune system is alarmed and assumes that tangled alpha-syn belongs to a pathogen that has infected the brain. The immune system dispatches T cells that are trained to specifically attack and eliminate “infected cells”. This is a huge mistake made by the immune system as there is no infection, just body’s own neurons making aberrant, tangled alpha-syn. These ‘killer” T cells in the circulation are attracted by the cytokine signals coming from the brain and cross blood brain barrier (which may be compromised due to neuro inflammation) to enter brain. They target neurons expressing tangled alpha-syn and kill them. This could be one way auto immune responses make neuro inflammation a continuous process as well as initiate specific and targeted killing of neurons. This hypothesis explains why certain neurons die while others survive.

Connecting the dots 4: PD and Prions
Mutated alpha-syn is not only sticky and tangled, but also becomes highly resistant to degradation. As neurons are dying, alpha-syn particles are released into the brain and these sticky protein particles spread from one neuron to another in a “PRION”-like fashion.

Connecting the dots 5: PD and Viral /bacterial infections
The immune system is trained not to attack its own body but selectively take out the invading pathogens. At the same time pathogens (virus, bacteria etc) make proteins that resemble body’s own proteins to evade/fool the immune system. Lets take influenza as an example. The antigens (degraded proteins) of influenza are constantly changing (reason for yearly vaccinations) to evade our immune system. Once again, using alpha-syn as an example, imagine influenza antigen that is a look alike of alpha-syn or tangled alpha-syn. Immune cells notice and respond to alpha-syn look-like viral protein and influenza virus is cleared by T cells. Infection is cleared, but T cells still see alpha-syn in the neurons and mistake that for persisting infection. Immune cells kill normal neurons and PD symptoms appear.

Girija

PS: Too many things to clean up to make it sound good. Hope you can see the general concept!