A Review of the Book Metal-Based Neurodegeneration

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.

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