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Sun Apr 10 20:50:42 EST 2005

>>From article <2np6m8$8aa at s.ms.uky.edu>,
>>by Steven W. Barger, Ph.D., posting from the account of
>>mpm at seqanal.mi.uky.edu (Mark Mattson):

>>> RSTETTA at DELPHI.COM (rstetta at news.delphi.com) wrote:
>>> : Looking for info on what Nuerotrophic Factors consist of,
>>> : and what effects them.

>>> : There is a form of muscular dystrophy, spinal muscle atrophy,
>>> : in which the motor nuerons are affected, weaken over time.
>>> : It is similiar to ALS (amyotrophic lateral sclerosis) but
>>> : progresses at a much slower rate.

Hmmm.  Now that I've done some reading on these subjects, I consider
myself qualified enough to correct some of the above statements.
First of all, I think it's incorrect to refer to spinal muscular
atrophy as "a form of muscular dystrophy".  SMAs are motor neuron
diseases, and as such are neuromuscular diseases, but they're not
muscular dystrophies.  Second, the distinction between ALS and SMA
is not necessarily rate of progression: in fact, I think that some
SMAs progress rather rapidly (confirmation, anyone?).  The main
difference between SMA and ALS is the fact that SMA specifically
affects *lower* motor neurons (i.e., spinal motor neurons) whereas
ALS affects both upper (i.e. cranial) and lower motor neurons.


>>> The prototype is nerve growth factor (NGF), now recognized as a member of
>>> a family of related peptides termed "neurotrophins" which all support the
>>> health and/or growth of neurons.  Different family members seem to be
>>> important for different types of neurons, but (as far as I know) none of
>>> these has been shown to be trophic for the motor neurons which are lost
>>> in ALS.  These cells may be more dependent on other factors produced by the
>>> muscles they innervate.

>>In fact, there is a young but rich literature indicating that at least one
>>of the neurotrophins (brain-derived neurotrophic factor, or BDNF) has a
>>profound trophic influence on exactly the motor neurons in question.

[deletion of citations and excerpts on BDNF's survival-promoting effects]

> Isn't there also evidence that CNTF (Ciliary Neurotrophic Factor) also
> rescues motor neurons?  I realize that CNTF does not belong to the same
> family of neurotrophins as does NGF, BDNF, NT-3 or NT-4/5 and that it
> does not act via any of the Trk's or by p75, the low-affinity
> neurotrophin receptor, but it is known to have neurotrophic effect,
> isn't that right?

Yes, that's right.  There's a very exciting and growing body of work on
this subject, culminating (IMHO) in the report last September that CNTF
knockout mice suffer from progressive atrophy and degeneration of motor
neurons, leading to "a small but significant reduction in muscle strength"
(Nature 365:27-32, 2 Sept. 1993).  Previous work had shown that CNTF
could rescue MNs from death under various life-threatening circumstances
(e.g. after axotomy); perhaps the most significant of these findings was
that CNTF could rescue MNs in mouse mutant progressive motor neuronopathy,
a mouse model of motor neuron disease (Nature 358:502-504 plus News &
Views pp. 451-2, 6 August 1992).

> If I am not mistaken, I think CNTF is found in high concentrations
> in Schwann cells, the glial cells that surround peripheral axons,
> so that the neurotrophin is released on axonal
> damage.  Aren't they also considering CNTF in the treatment of ALS?

Sounds right, but perhaps our Regeneron colleagues can confirm this.

I think that last month's issue of Neuron had a paper demonstrating
the increased retrograde transport of CNTF after axonal damage.

> Being more of an intracellular signal transduction kinda guy myself,
> I know more about the signaling pathway of CNTF than I know what it's
> good for.  ;-)  If you want to know like *I* wanted to know, check out
> A Bonni et al. in last December's _Science 262_: 1575-9.  That's the
> December 3rd issue, if you happen to subscribe.  Or if your library
> hasn't gotten around to binding that week's issue.  It seems to signal
> through the JAK-STAT pathway...

I got some email from a scientist at Regeneron informing me that
CNTF and BDNF act synergistically (published?) and speculating that
this is due to overlap in the downstream signalling cascades.

Steve Matheson   Program in Neuroscience   University of Arizona
sfm at neurobio.arizona.edu

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