Re: How does MPP+ cause the death of dopamine receptors in the substantia nigra

The mechanism for the neurotoxicity of MPP+ is a very important question 
that lots of people are working on very hard.  While the complete answer is 
still not available, lots of progress has been made in the past few years - 
which I will now discuss.  But first, allow me (for readers not entirely 
familiar with this subject) to give a bit of background.

It all started in Northern California in the early 80's when a large group 
of heroin addicts developed Parkinson's disease.  Parkinson's disease 
(let's call it PD for short) is a relatively common neurological disease 
(500,000 Americans have it) that results in involuntary motion, tremors, 
balance/gait problems, muscle slowness and rigidity, inability to initiate 
motion, etc.  The symptoms of PD range from the very severe (like in the 
movie "Awakenings") to the very mild (as in Michael J. Fox, for example).  
In all cases, the problem seems to be the death of neurons in a tiny region 
of the brain called the substantia nigra (which is located at the very base 
of the brain near where the spinal chord enters).  These neurons are 
referred to as dopaminergic since they release the neurotransmitter 
dopamine when they are electrically stimulated.  Dopamine is one of the 
monoamine neurotransmitters (similar chemically to serotonin and 
acetlycholine, for example).  The symptoms of PD are due to the fact that 
these neurons in the substantia nigra are important for communication 
between the motor cortex (which controls muscle movement) and the 
somatosensory cortex (which handles sensory input).   That is they take 
information about the positions of your arms (for example) and figure out 
what types of muscle movements need to occur to move your arms into the 
position that you desire.  When these dopaminergic neurons die, this 
important line of communication is shut down and the symptoms result.

So what does this have to do with heroin addicts?  Well, it turns out that 
even though we know that PD is caused by the death of certain brain cells, 
we don't know WHY they die in the first place.  We know that in some cases 
(say about 20% or so) it is probably genetic, but in other cases there are 
probably environmental causes - like some sort of chemical toxin.  So when 
scientists discovered that a rather large group of heroin addicts came down 
with PD, they decided to figure out why.  As it turned out, the heroin that 
these people were using had a chemical contaminant called MPTP.  If you 
inject MPTP into a monkey, for example, it will develop PD.  When they 
autopsied these monkeys, scientists realized that all of the dopaminergic 
neurons in the substantia nigra had died.  So, for the first time ever, 
scientists found a chemical that causes PD.

So how does MPTP kill these neurons?  The fact is that it doesn't - it 
needs to first be converted to another chemical called MPP+.  This occurs 
in the brain because of the presence of an enzyme called monoamine oxidase 
(MAO for short).  The normal job of this enzyme is to oxidize dopamine (to 
remove it because dopamine itself is toxic to the neurons).  Once this 
conversion takes place, MPP+ is transported into the dopaminergic neurons. 
 This happens because the dopamine transporter (which normally transports 
dopamine back into the neurons after it has been released) can also 
transport MPP+ (but not MPTP).  Once MPP+ gets inside the cell, it binds to 
complex I of the oxidative phosphorylation chain in the mitochondria and 
irreversibly inhibits this process.  While this inhibition causes a 
decrease in the amount of ATP that the mitochondria produce, this is not 
thought to actually kill the cell.  Blocking complex I causes another much 
more serious problem - the production of oxygen free radicals.

Oxygen free radicals are very bad molecules.  Because of their destructive 
reactivity, they can destroy proteins and DNA.  However, the cell has all 
sorts of mechanisms for soaking up oxygen free radicals when they are 
produced.  And in fact, it has been shown that oxygen free radicals are 
still not enough to kill the dopaminergic neurons of the substantia nigra.  
What also has to happen is the production of nitric oxide (NO), which 
unfortunately these cells constantly do.  In fact, it has been shown that 
if you take away the enzyme that makes NO, MPP+ is no longer toxic at all! 
 What is now believed to happen is that oxygen free radicals and NO combine 
to form peroxynitrite, which is a REALLY BAD molecule.  This highly 
reactive molecule readily causes double strand DNA breaks (the worst kind 
of DNA damage).

When the cell accumulates too much DNA damage to repair, it realizes that 
the end is near and it decides to commit suicide in a "clean" way so as not 
to damage neighboring cells.  This process is called programmed cell death 
or apoptosis.  This is how the cells actually die - on their own terms.  
MPP+ just pushes them to make this decision.  

So why is it so important to study how MPTP kills neurons?  It is because 
it is possible that the natural causes of PD may have a similar mechanism 
to MPTP.  If scientists are able to figure out how MPTP works, they may be 
able to find ways to interfere with this process and stop the progression 
of normal PD.  In fact, one simple possibility is to find MAO inhibitors, 
since these should prevent molecules similar to MPTP to be converted into 
forms similar to MPP+ which can be transported into neurons.  It now seems 
that in some cases, at least, MAO inhibitors do indeed help slow down the 
progression of PD.

I hope this answered most of your questions.  The following two references 
can give you more information…

1. Principles of Neural Science by Kandel, Schwartz, and Jessell.  (1991).

2. Mandir et al., Proc. Natl. Acad. Sci. USA, Vol. 96, pp. 5774-5779.  
(1999).