[lurkingforacure]

OK, I'm going to assume for this question that PD is caused, in whole or in part, by a leaky BBB. For whatever reason, stress, inflammation, unrelated illness, the BBB opens up and starts letting bad stuff in. This goes on, and on, and on, until PD symptoms appear.

So my question is: why aren't other parts of the brain affected by this? Why is it only the substantia nigra that shows the loss/damage of cells in PD? I would think, if bad things were coming in when the BBB opened up, time and after time after time, that the entire brain would be affected...but I have never read anywhere that they have found this to be the case on postmortem examination. To the contrary, it is only this finite, tiny little area that appears affected, by loss/damage of neurons, and alpha-synuclein tangles (Lewy bodies).

I'm welcoming any comments if I have missed or misunderstood anything.

[reverett123]

1- Prenatal exposure to bacterial toxin LPS sets up hypersensitivity post-puberty to further exposure. The reaction is activation of innate immune response of activation of microglia which is sustained far longer than desired and kills neurons.
2- Breaching of BBB allows entry of toxins, one of which is LPS which is ever present with a fluctuating level. Entry of LPS into brain drives microglia ape. The highest density of microglia is in the substantia nigra, thus damage is greatest there.
3- LPS has a synergistic effect with several of the suspects in PD and breach of BBB could allow entry of multiple insults, rotenone for example. But there has to be something more about the SN to make that the main area impacted. My money is on iron at the moment.

Originally Posted by lurkingforacure

OK, I'm going to assume for this question that PD is caused, in whole or in part, by a leaky BBB. For whatever reason, stress, inflammation, unrelated illness, the BBB opens up and starts letting bad stuff in. This goes on, and on, and on, until PD symptoms appear.

So my question is: why aren't other parts of the brain affected by this? Why is it only the substantia nigra that shows the loss/damage of cells in PD? I would think, if bad things were coming in when the BBB opened up, time and after time after time, that the entire brain would be affected...but I have never read anywhere that they have found this to be the case on postmortem examination. To the contrary, it is only this finite, tiny little area that appears affected, by loss/damage of neurons, and alpha-synuclein tangles (Lewy bodies).

I'm welcoming any comments if I have missed or misunderstood anything.

[paula_w]

that seems true lfac, but they have found lewy bodies in other parts of the body. this was presented by Langston 2 years ago at PAN -it was somewhere like the gut or intestines...i'll try to remember to look it up. could be even more places. he said it in his first public presentation to patients of the new PD definitions.

paula

[girija]

Here is my attempt to answer your Q: it is a working hypothesis!
Leaky BBB facilitates the transport of neuronal specific proteins in substantia nigra to the periphery. Immune system specially T cells that are activated by earlier viral infections mistake this neuronal antigen for a viral antigen (molecular mimicry). Activated T cells go looking for cells infected with the "virus". Leaky BBB enables their passage to brain. T cells find neurons with the viral protein" they are looking for and so they destroy neurons.
Leaky BBB also allows various substances into brain, toxins randomly activate microglia which make inflammatory cytokines. These cytokines in turn, keep T cells under constant activation and the cycle of neuronal death continues.

There is enough data to support each of these observations independently, but not as a complete story.

What we know so far:
T cells are found in the nigra area, microglia are activated, cytokines are seen

What we dont know is : For example if alpha syn is the protein which T cells are recognizing, does it have any homology to any proteins from pathogens
What is unique to nigra neurons from immunological point?
There would be more questions as the story develops!

This hypothesis can be tested easily, just have to start on the project! I am going blame PD-related inertia for that!

Girija

Girija

QUOTE=lurkingforacure;476625]OK, I'm going to assume for this question that PD is caused, in whole or in part, by a leaky BBB. For whatever reason, stress, inflammation, unrelated illness, the BBB opens up and starts letting bad stuff in. This goes on, and on, and on, until PD symptoms appear.

So my question is: why aren't other parts of the brain affected by this? Why is it only the substantia nigra that shows the loss/damage of cells in PD? I would think, if bad things were coming in when the BBB opened up, time and after time after time, that the entire brain would be affected...but I have never read anywhere that they have found this to be the case on postmortem examination. To the contrary, it is only this finite, tiny little area that appears affected, by loss/damage of neurons, and alpha-synuclein tangles (Lewy bodies).

I'm welcoming any comments if I have missed or misunderstood anything.[/QUOTE]