why the substantia nigra

[Guest guest]

If you're like me, you're like: wow, Parkinson's... movement problems,

depression... brain seems messed up, so that much definitely

tallies... but why the dopaminergic neurons of the substantia nigra,

in particular? (Though I think norepinepherinergic neuron loss is an

emerging subject in Parkinson's.)

Similarly, why the white matter for certain kinds of lesions in other

neurodegenerative 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 RA

often symmetric? Why would that happen?

Here at last I have learned a little of why the DAergic neurons of the

black matter... c/o PLoS Biology:

" It remains a mystery why the impaired phosphorylation of TRAP1 by

mutated PINK1 induces the specific DA neurodegeneration seen in PD.

PINK1 is not limited to DA neurons of the substantia nigra, but is

expressed throughout the human brain in all cell types, as well as

outside the brain, and the same applies to TRAP1 [17]. "

These are proteins which, when mutated, can be associated with

early-onset Parki's. It is generally similar to, but can be a bit

different from, the classic, commoner late-onset form, which occurs in

1% of the over-50 population and is not strongly associated with any

mutations, to my knowledge. Basically it's comparable to Alz, which

has a common form with no strong causation from any single allele, and

also 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 oxidative

stress is a hallmark of the damaged substantia nigra from PD patients.

The preferential loss of nigral neurons in PD has been attributed to

the highly oxidative intracellular environment in dopaminergic neurons

[18]. Oxidation and degradation of the labile transmitter dopamine may

induce oxidative stress, proteolytic dysfunction, and mitochondrial

defects, and this may be the underlying reason for the selective

vulnerability of DA neurons [19]. Oxidative stress is intimately

linked to other aspects of neurodegeneration, such as mitochondrial

dysfunction, which may make it difficult to determine whether

oxidative stress leads to, or is a consequence of, mitochondrial

dysfunction [etc] "

Now it starts to make sense. Bring in MPP+, a drug (don't try this

one) that's well known to induce a parkinsonism... a state quite

consonant with classic (late onset) Parkinson's, though I'm guessing

it's at least a little different:

" Furthermore, the toxicity of mitochondrial poisons such as

1-methyl-4-phenylpyridium ions (MPP+) and rotenone is most pronounced

in DA neurons, even though they inhibit complex I throughout the

brain, suggesting that DA neurons are intrinsically sensitive to

complex I defects [20]. [...]

" As a result, deficient PINK1 function might selectively affect DA

neurons, because DA neurons constitute the cell type that is most

susceptible to ROS attack in the human body. "

Kroemer G, Blomgren K (2007) Mitochondrial Cell Death Control in

Familial Parkinson Disease. PLoS Biol 5(7): e206

http://biology.plosjournals.org/perlserv/?request=get-document & doi=10.1371/journ\

al.pbio.0050206