<<snip>>
It is more than a coincidence that iron is found to such a large
extent in the basal ganglia,
<<snip>>.
A Review of the Book Metal-Based Neurodegeneration: From Molecular
Mechanisms to Therapeutic Strategies
by Robert Crichton and Roberta Ward
-- Malcolm Casale, Ph.D. [ print-friendly ]
A Review of the Book Metal-Based Neurodegeneration: From Molecular
Mechanisms to Therapeutic Strategies by Robert Crichton and Roberta
Ward
Malcolm Casale, Ph.D.
First of all, it is very good to be doing this review. It's not every
day that a book comes out on neurodegenerative diseases, especially
one that covers Huntington's (HD), and it is a very good book at
that.
The book is based on a powerful premise, though this premise is
clearly stated only in the concluding remarks. Paraphrasing, the
premise is that a clear path leads from (i) metal-based oxidative
stress in the brain, through (ii) the production of harmful reactive
molecules (Reactive Oxygen Species, or ROS), which themselves then
(iii) cause damage to proteins, such that (iv) the proteins accumulate
in beta-sheet-rich aggregates, because (v) these proteins fail to be
cleared by cellular waste disposal mechanisms.
The book is exciting, not so much because of its coverage of HD,
although it does devote a chapter to HD, but because of its coverage
of metal-based neurodegeneration in general. The diseases it explores,
besides HD, includes Alzheimer's Disease, amyotrophic lateral
sclerosis, prion diseases, and others that have all been recently
found to share features of oxidative stress and beta-sheet-rich
oligomerization (small clumps of protein fragments). Our hope is that
researchers who concentrate on one of these diseases might extend
their conceptual scope in reading the book, noting similarities and
differences between their own research areas and HD, engendering new
perspectives on old problems. Sharpening the understanding of metal-
based neurodegeneration could lead to treatments for HD.
Regarding oxidative stress: We've all heard of free radicals. These
are molecules that are split by natural processes (notably, within
mitochondria) and temporarily have an unpaired electron. One of the
principles of chemistry is that electrons tend to come in pairs.
Hence, free radicals react with surrounding molecules, stealing their
electrons, causing them to become free radicals themselves, in a chain
reaction that can be harmful to the cell, for example, by damaging
DNA. Antioxidants stop this chain reaction by donating a free
electron, and in such a way that they remain stable themselves.
Ordinarily, a cell holds sufficient antioxidants to counter the
harmful effects of free radicals, but when it does not, oxidative
stress occurs. In oxidative stress, the antioxidant capabilities of a
cell are overwhelmed, and remaining unpaired free electrons can then
damage cell components.
How do metals enter the picture? First, metals perform many vital
functions in the brain, including transmitter synthesis. (See Beard,
1999, for a review of iron in the brain [1].) But they also,
especially iron, participate in reactions that generate free radicals,
thus potentially increasing the free radical load of the cell. This is
why the body takes such pains to sequester iron in ferritin, a
remarkable, hollow protein complex that encloses and carries iron
molecules to exactly where they are needed (for more on ferritin and
HD, click here for HDL article on ferritin ). When iron is bound in
ferritin, it cannot participate in reactions that produce free
radicals.
Crichton and Ward begin their book reviewing the essential functions
of metals in the brain. Iron gets top billing, but other metals are
also important. These include copper, zinc, and others. All play
important roles in neurochemistry. Iron is especially notable due to a
reaction in which it participates, the Fenton reaction, in which the
iron catalyzes the production of a free radical called the hydroxyl
radical. It is just for this reason that the cell carefully regulates
iron, sequestering it within ferritin until it is needed by
mitochondria or other organelles.
Next, the book takes the reader through various neurodegenerative
diseases Parkinson's, Alzheimer's, HD, prion (mad cow) disease, and
others - pointing out their common and unique features. The section on
HD is a useful reference, though it does not cover the disease in
depth. As noted above, the book's main value to us, people primarily
interested in HD, is in its clarification of the molecular machinery
common to many metal-based neurodegenerative diseases, even more than
in its coverage of HD itself. After considering a variety of diseases,
the authors shift to animal models and conclude with therapeutic
strategies. What finally emerges is the authors' overarching picture
the proposed five steps in the causal path of metal-based
neurodegeneration (the five steps listed in this review above, first
paragraph, and again below).
The reader should be aware of a few points regarding this generally
useful new book. First, large parts of the book actually have little
to do with metals. The book might have been better titled just
"Neurodegeneration." We would have liked to see more explicit links
made between metals and neurodegenerative processes throughout the
document, although ROS, often generated by metal-catalyzed reactions,
do play a prominent role throughout the text.
Another point is that the book's conclusions could be helpfully
qualified. Rather than representing a clear path leading from (i)
metal-based oxidative stress in the brain, through (ii) production of
harmful reactive molecules (ROS), which themselves then (iii) damage
proteins, (iv) causing them to accumulate, it is clear that HD, at
least, is initially caused by a misfolded (or at least altered)
protein, huntingtin. This leads to oxidative stress (somehow), which
is probably accelerated by iron and other events.
These points notwithstanding, the book is generally well done. Our own
work (Simmons, et al., 2005), and the work of many other researchers,
lends credence to the notion that HD is among the metal-based
neurodegenerative diseases - the book's thesis is clearly of
importance to HD research. It is more than a coincidence that iron,
for example, is found to such a large extent in the basal ganglia, the
region most affected in HD. (It was this observation that led Dr.
LaVonne Goodman, principal in the HD Lighthouse and Huntington's
Disease Drug Works, to sponsor the low-iron diet study referenced
below [2].)
While the exact role of metals in HD pathology remains to be
determined, the new book by Crichton and Ward is a useful addition to
the libraries of researchers in their search for therapeutics for HD
and other neurodegenerative diseases. For those of us affected by HD,
the book may be, some years from now, looked back on as a milestone.
It was only in 1993 that the HD gene was identified. Then came
discoveries relating to beta-sheet formation, genetically altered HD
(R6/2) mice, nuclear inclusions, and many other knowledge advances. As
this new book shows, recent findings indicate that many
neurodegenerative diseases share a lot in common at the molecular
level. HD has become one in a critical family of research areas, in
which a benefit to one may be a benefit for all.
References: 1. J. L. Beard. Iron deficiency and neural development: an
update. Arch Latinoam Nutr. 1999 Sep;49(3 Suppl 2):34S-39S. (For the
abstract, click here.)
2. D. A. Simmons, M. Casale, B. Alcon, N. Pham, N. Narayan, and G.
Lynch. Increased ferritin in reactive microglia is present early in
striatum of Huntington's Disease patients and R6/2 mice. Society for
Neuroscience, 2005. Reviewed on the Lighthouse - click here.
Source: Wiley, 2006.
- published 04-25-2006
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