HD Lighthouse Contributing Editor's Comment: The abstract below talks about the discovery of highly increased amounts of ferritin, a molecule that carries iron, in HD mice and tissue from symptomatic individuals. Iron is crucial to cellular function, but it also catalyzes the generation of free radicals and can, therefore, be very dangerous. The body goes to exquisite lengths to shephard iron through the cell, using the protein ferritin as a carrier. Ferritin is a hollow, spherical assembly (Figure 1) that can hold up to 4500 iron atoms, deliverying them to where they are needed, safe and secure. What the study below shows is that ferritin is strongly elevated in the brains of the famous R6/2 mice, which are the most popular animal model of HD. This elevation was observed as early as two weeks, before the mice pups are even weened. Furthermore, the ferritin staining occurs in cells called microglia, causing these cells to light up the way they do when they are activated. This is highly suggestive of an immune/inflammatory response. The finding in mice led the scientists to check for similar findings in human tissue. Sure enough, human HD brains in symptomatic individuals showed similar characteristics. It will be very interesting to look for inflammation in presymptomatic brains. However, tissue from presymptomatic individuals is very rare and precious, and is, therefore, highly regulated. So, it will be some time before these results are in. What does it all mean? Several things. First of all, it may be that the elevated iron is contributing to HD. Compounds known as iron chelators are availble to treat this phenomenon. Such compounds are now being evalulated for their effect in HD. Second, the inflammatory response, which is the body's way of responding to injury, can sometimes go awry. Hence, treating inflammation early in the disease course may stave off symptoms. Numerous drugs that affect inflammation are available, and these are being investigated. If the results of early inflammation in mice carry over to presymptomatic humans, then it may be that compounds could be given to individuals at risk to postpone the ravaging affects of the disease.

Lastly, we must point out that the findings below were due to a serrendipitous discovery made during a study suggested by HDLighthouse contributing editor, Dr. LaVonne Goodman. Dr. Goodman noted that iron may be involved in HD pathology, and her organization, the Huntington's Disease Drug Works (HDDW) funded a low-iron dietary study in which the finding occurred. We are indebted to her and the HDDW.
--Malcolm Casale, Ph.D.
Posted to the HDL: 27 Jul 2005

D.A.Simmons, M.Casale, B.Alcon, N.Pham, N.Narayan,G.Lynch

Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by motor and cognitive deficits. The hallmark neuropathologies of HD are nuclear inclusions of huntingtin and neuronal death in the striatum and cerebral cortex. HD patients also show increased reactive microglia and iron in the striatum. As a first step to determining the role of inflammation and iron in HD pathogenesis, reactive microglia and ferritin, an iron storage protein, were investigated in R6/2 mice and HD patients at several stages of disease progression. Brains from R6/2 mice at 2 week intervals ranging from 2 to 16 weeks and HD patients (Vonsattel Grades 2-4) were processed immunocytochemically for reactive microglia (IBA1 antibody) and ferritin, and compared to age-matched controls. In both wild-type (WT) and R6/2 mice, ferritin immunostaining was present mainly in small cells resembling reactive microglia. At as early as 2 wks, these dendritic-like cells had more processes that had bulges and were thicker and twisted in R6/2 compared to WT mice. At each age range examined, the area of ferritin staining in the striatum was greater (2-5.5 times) in R6/2 than WT mice (p < 0.05). R6/2 mice only showed increased IBA1 staining at 11-13 wks. In striatum of HD patients, the area of ferritin- and IBA1-stained microglia was larger (2 and 1.5 times, respectively) at Vonsattel grades 2-4 compared to controls (p < 0.05). Additionally, many microglia appeared dystrophic and had bulges on their processes that contained iron, as assessed by combining IBA1 staining and Perl’s reaction for iron. Compared to controls, HD patients also had more immunostaining for major histocompatibility complex I suggesting the microglia may be antigen-presenting cells. Since ferritin is increased in reactive microglia that appear dystrophic before the onset of behavioral deficits in R6/2 mice and in early stage HD, dysfunctional microglia and disruption of iron homeostasis may contribute to HD pathogenesis. Supported by HD Drug Works and Thuris Corp.

Tracked on the Lighthouse:
ferritin
iron
inflammation
microglia

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Source: paper to be presented at the November 2005 Neuroscience conference.

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