Re: why the substantia nigra

[Guest guest]

Okay, so I didn't get any of that. But then I'm having trouble concentrating. Did you figure anything out about the symmetric joint issues? I've always wondered about this too. Stiffness in my ankles first appeared around 20 years ago which is why I suspected lyme disease back then (ankle stiffness is one of the symptoms) but I tested negative then (and again more recently). My original ankle stiffness went away after a few months but reappeared about a year ago. Now both of my ankles are extremely stiff most of the time. I also have pretty serious problems with both shoulders (rotator cuff tendonitis). Why does an infection sometimes affect identical locations on opposite sides of the body? I suppose you could ask why do people sometimes lose their sight in both eyes or hearing in both ears as well? penny

<usenethod@...> wrote: If you're like me, you're like: wow, Parkinson's... movement problems,depression... brain seems messed up, so that much definitelytallies... but why the dopaminergic neurons of the substantia nigra,in particular? (Though I think norepinepherinergic neuron loss is anemerging subject in Parkinson's.) Similarly, why the white matter for certain kinds of lesions in otherneurodegenerative diseases.This is a stimulating question re pathogenesis in a broader sense...why any lesion

pattern, in any disease. Why is the lesion located at<x,y,z> rather than 2 cm to the right? Why is joint involvement in RAoften symmetric? Why would that happen?Here at last I have learned a little of why the DAergic neurons of theblack matter... c/o PLoS Biology:"It remains a mystery why the impaired phosphorylation of TRAP1 bymutated PINK1 induces the specific DA neurodegeneration seen in PD.PINK1 is not limited to DA neurons of the substantia nigra, but isexpressed throughout the human brain in all cell types, as well asoutside the brain, and the same applies to TRAP1 [17]."These are proteins which, when mutated, can be associated withearly-onset Parki's. It is generally similar to, but can be a bitdifferent from, the classic, commoner late-onset form, which occurs in1% of the over-50 population and is not strongly associated with anymutations, to my knowledge. Basically it's comparable to Alz,

whichhas a common form with no strong causation from any single allele, andalso rarer forms of earlier onset which require certain mutation(s).So anyway..."A second integral feature of PD pathogenesis is oxidative stress.Postmortem investigations have consistently shown that oxidativestress is a hallmark of the damaged substantia nigra from PD patients.The preferential loss of nigral neurons in PD has been attributed tothe highly oxidative intracellular environment in dopaminergic neurons[18]. Oxidation and degradation of the labile transmitter dopamine mayinduce oxidative stress, proteolytic dysfunction, and mitochondrialdefects, and this may be the underlying reason for the selectivevulnerability of DA neurons [19]. Oxidative stress is intimatelylinked to other aspects of neurodegeneration, such as mitochondrialdysfunction, which may make it difficult to determine whetheroxidative stress leads to, or is a

consequence of, mitochondrialdysfunction [etc]"Now it starts to make sense. Bring in MPP+, a drug (don't try thisone) that's well known to induce a parkinsonism... a state quiteconsonant with classic (late onset) Parkinson's, though I'm guessingit's at least a little different:"Furthermore, the toxicity of mitochondrial poisons such as1-methyl-4-phenylpyridium ions (MPP+) and rotenone is most pronouncedin DA neurons, even though they inhibit complex I throughout thebrain, suggesting that DA neurons are intrinsically sensitive tocomplex I defects [20]. [...] "As a result, deficient PINK1 function might selectively affect DAneurons, because DA neurons constitute the cell type that is mostsusceptible to ROS attack in the human body." Kroemer G, Blomgren K (2007) Mitochondrial Cell Death Control inFamilial Parkinson Disease. PLoS Biol 5(7): e206http://biology.plosjournals.org/perlserv/?request=get-document & doi=10.1371/journal.pbio.0050206

[Guest guest]

Sorry... I scribbled that whole thing in my own interior technobabble

at 90 miles a minute. Sometimes I write stuff mainly for my own

benefit, because writing really hard-wires it into my long-term

memory. And then I just want to post it somewhere in case someone

wants to read it.

Basically they said that the dopaminergic neurons of the brain are, by

nature, the neurons most sensitive to oxidative stress. So it would be

no shock if normal Parkinson's involves oxidation that ends up zapping

these DAergic neurons selectively (but it's not totally clear that

that is the correct sequence of events).

MPP+ is a toxic drug which has been tried in man, by accident, at

least one time - it was a contaminant once in a batch of synthetic

street heroin. The people who took it contracted a serious

parkinsonism syndrome. It does the same in the mouse.

I once had a friend who handled MPP+ in research labwork regularly, as

an undergrad - yikes, be careful with that shit. I think they said in

the article that MPP+ causes oxidative stress by messing up the

metabolism of the respiratory chain, but I am not sure I have that

quite correct.

Hearing loss - I've no idea.

More later, gotta go......

>

> Okay, so I didn't get any of that. But then I'm having trouble

concentrating. Did you figure anything out about the symmetric joint

issues? I've always wondered about this too. Stiffness in my ankles

first appeared around 20 years ago which is why I suspected lyme

disease back then (ankle stiffness is one of the symptoms) but I

tested negative then (and again more recently). My original ankle

stiffness went away after a few months but reappeared about a year

ago. Now both of my ankles are extremely stiff most of the time. I

also have pretty serious problems with both shoulders (rotator cuff

tendonitis). Why does an infection sometimes affect identical

locations on opposite sides of the body?

>

> I suppose you could ask why do people sometimes lose their sight

in both eyes or hearing in both ears as well?

>

> penny

>

[Guest guest]

Regarding symmetry in arthritis... well, the first thing you think of

is, is there a specific molecule in the joint that a pathogen could

interact with. A virus needs a specific receptor, a bacterium usually

needs something to bind to, a T cell seeks a specific peptide to

trigger cytokine release. Any of those could be pathogenic agents. But

is there a unique molecule expressed only in the second joint of the

index finger, or one expressed only in the ankle? I don't know.

Another possibility is that the nervous system is involved. There is a

good bit of interesting work on nervous involvement in mouse diabetes,

experimental autoimmune mouse arthritis, etc. It's been a few years

but I seem to recall something about certain forms of one-sided

experimental arthritis causing a bit of an inflammatory " echo " at the

same anatomical site on the opposite side of the body.

The injury-associated immune disease sympathetic ophthalmia is of

interest in this connection. It seems most likely to be an immune

reaction against eye tissues (or perhaps eye-dwelling microbes???)

exposed by injury to the immune system - usually the eye is a

" privileged site " with little interaction with the immune system, much

like the brain.

These privileges probably evolve, I think, because most pathogens have

little interest in infecting the eye or brain - delicate structures

whose demise will rapidly kill the host - and because the host cannot

really benefit from " going nuclear " (or anywhere close) on a pathogen

that does end up in the eye or brain (which may be an " accident " as

often as not). There may also be a bit of runaway positive feedback,

evolutionarily, between the three factors - host reluctance to damage

the brain, pathogen reluctance to damage the brain, and the delicacy

of the organ (I suspect organs should " want " to be delicate in the

absence of countervailing forces, because it allows them to develop

more sophisticated designs more easily with more latitude). The more

privileged the brain already is, the more it will tend to evolve

delicate structure and function, the less a microbe wants to behave

virulently in the brain, etc.

I am not sure how well this model of immune privilege handles the

testis. And are the uterus and ovaries also privileged, I don't know.

Anyway, the neat thing about sympathetic ophthalmia is that its spread

to the opposite eye evidently can be prevented by rapid removal of the

damaged eye. It's quite fascinating, but I don't know much about it.

Wikipedia knows much more about it than me. In this case, it is

certain that there are special molecules found only in the eye, which

could explain why the disease is eye-specific, whatever the

involvement of microbes, lymphocytes, etc, may be.

> More later, gotta go......

> > Okay, so I didn't get any of that. But then I'm having trouble

> concentrating. Did you figure anything out about the symmetric joint

> issues? I've always wondered about this too. Stiffness in my ankles

> first appeared around 20 years ago which is why I suspected lyme

> disease back then (ankle stiffness is one of the symptoms) but I

> tested negative then (and again more recently). My original ankle

> stiffness went away after a few months but reappeared about a year

> ago. Now both of my ankles are extremely stiff most of the time. I

> also have pretty serious problems with both shoulders (rotator cuff

> tendonitis). Why does an infection sometimes affect identical

> locations on opposite sides of the body?

> >

> > I suppose you could ask why do people sometimes lose their sight

> in both eyes or hearing in both ears as well?

> >

> > penny

> >

>

[Guest guest]

Bugs take avantage of bad circulation- dehyration ..if you could keep

things flowing without stagnation you'd be a ok.IMO

>

>

> Regarding symmetry in arthritis... well, the first thing you think

of

> is, is there a specific molecule in the joint that a pathogen could

> interact with. A virus needs a specific receptor, a bacterium

usually

> needs something to bind to, a T cell seeks a specific peptide to

> trigger cytokine release. Any of those could be pathogenic agents.

But

> is there a unique molecule expressed only in the second joint of the

> index finger, or one expressed only in the ankle? I don't know.

>

> Another possibility is that the nervous system is involved. There

is a

> good bit of interesting work on nervous involvement in mouse

diabetes,

> experimental autoimmune mouse arthritis, etc. It's been a few years

> but I seem to recall something about certain forms of one-sided

> experimental arthritis causing a bit of an inflammatory " echo " at

the

> same anatomical site on the opposite side of the body.

>

> The injury-associated immune disease sympathetic ophthalmia is of

> interest in this connection. It seems most likely to be an immune

> reaction against eye tissues (or perhaps eye-dwelling microbes???)

> exposed by injury to the immune system - usually the eye is a

> " privileged site " with little interaction with the immune system,

much

> like the brain.

>

> These privileges probably evolve, I think, because most pathogens

have

> little interest in infecting the eye or brain - delicate structures

> whose demise will rapidly kill the host - and because the host

cannot

> really benefit from " going nuclear " (or anywhere close) on a

pathogen

> that does end up in the eye or brain (which may be an " accident " as

> often as not). There may also be a bit of runaway positive feedback,

> evolutionarily, between the three factors - host reluctance to

damage

> the brain, pathogen reluctance to damage the brain, and the delicacy

> of the organ (I suspect organs should " want " to be delicate in the

> absence of countervailing forces, because it allows them to develop

> more sophisticated designs more easily with more latitude). The more

> privileged the brain already is, the more it will tend to evolve

> delicate structure and function, the less a microbe wants to behave

> virulently in the brain, etc.

>

> I am not sure how well this model of immune privilege handles the

> testis. And are the uterus and ovaries also privileged, I don't

know.

>

> Anyway, the neat thing about sympathetic ophthalmia is that its

spread

> to the opposite eye evidently can be prevented by rapid removal of

the

> damaged eye. It's quite fascinating, but I don't know much about it.

> Wikipedia knows much more about it than me. In this case, it is

> certain that there are special molecules found only in the eye,

which

> could explain why the disease is eye-specific, whatever the

> involvement of microbes, lymphocytes, etc, may be.

>

>

>

>

> > More later, gotta go......

>

>

>

>

> > > Okay, so I didn't get any of that. But then I'm having trouble

> > concentrating. Did you figure anything out about the symmetric

joint

> > issues? I've always wondered about this too. Stiffness in my

ankles

> > first appeared around 20 years ago which is why I suspected lyme

> > disease back then (ankle stiffness is one of the symptoms) but I

> > tested negative then (and again more recently). My original ankle

> > stiffness went away after a few months but reappeared about a year

> > ago. Now both of my ankles are extremely stiff most of the time. I

> > also have pretty serious problems with both shoulders (rotator

cuff

> > tendonitis). Why does an infection sometimes affect identical

> > locations on opposite sides of the body?

> > >

> > > I suppose you could ask why do people sometimes lose their

sight

> > in both eyes or hearing in both ears as well?

> > >

> > > penny

> > >

> >

>