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Targeting Iron Dyshomeostasis for Treatment of Neurodegenerative Disorders

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Abstract

While iron has an important role in the normal functioning of the brain owing to its involvement in several physiological processes, dyshomeostasis has been found in many neurodegenerative disorders, as evidenced by both histopathological and imaging studies. Although the exact causes have remained elusive, the fact that altered iron levels have been found in disparate diseases suggests that iron may contribute to their development and/or progression. As such, the processes involved in iron dyshomeostasis may represent novel therapeutic targets. There are, however, many questions about the exact interplay between neurodegeneration and altered iron homeostasis. Some insight can be gained by considering the parallels with respect to what occurs in healthy aging, which is also characterized by increased iron throughout many regions in the brain along with progressive neurodegeneration. Nevertheless, the exact mechanisms of iron-mediated damage are likely disease specific to a certain degree, given that iron plays a crucial role in many disparate biological processes, which are not always affected in the same way across different neurodegenerative disorders. Moreover, it is not even entirely clear yet whether iron actually has a causative role in all of the diseases where altered iron levels have been noted. For example, there is strong evidence of iron dyshomeostasis leading to neurodegeneration in Parkinson’s disease, but there is still some question as to whether changes in iron levels are merely an epiphenomenon in multiple sclerosis. Recent advances in neuroimaging now offer the possibility to detect and monitor iron levels in vivo, which allows for an improved understanding of both the temporal and spatial dynamics of iron changes and associated neurodegeneration compared to post-mortem studies. In this regard, iron-based imaging will likely play an important role in the development of therapeutic approaches aimed at addressing altered iron dynamics in neurodegenerative diseases. Currently, the bulk of such therapies have focused on chelating excess iron. Although there is some evidence that these treatment options may yield some benefit, they are not without their own limitations. They are generally effective at reducing brain iron levels, as assessed by imaging, but clinical benefits are more modest. New drugs that specifically target iron-related pathological processes may offer the possibility to prevent, or at the least, slow down irreversible neurodegeneration, which represents an unmet therapeutic target.

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  1. Niels Bergsland and Eleonora Tavazzi contributed equally to the work.

Authors and Affiliations

  1. Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 100 High St., Buffalo, NY, 14203, USA

    Niels Bergsland, Eleonora Tavazzi, Ferdinand Schweser, Dejan Jakimovski, Jesper Hagemeier, Michael G. Dwyer & Robert Zivadinov

  2. Center for Biomedical Imaging, Clinical and Translational Science Institute, University at Buffalo, State University of New York, Buffalo, NY, USA

    Ferdinand Schweser, Michael G. Dwyer & Robert Zivadinov

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This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health, under award Number UL1TR001412. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest

Niels Bergsland, Eleonora Tavazzi, Dejan Jakimovski, and Jesper Hagemeier have no conflicts of interest that are directly relevant to the content of this article. Ferdinand Schweser has received personal compensation from Toshiba Canada Medical Systems Limited, Canon Medical Systems Corporation Japan, and Goodwin Procter LLP for speaking and consultant fees. He received financial support for research activities from SynchroPET Inc. and travel sponsorship from GE Healthcare and SynchroPET Inc. Michael G. Dwyer has received consultant fees from Claret Medical and research grant support from Novartis. Robert Zivadinov has received personal compensation from EMD Serono, Genzyme-Sanofi, Novartis, and Celgene for speaking and consultant fees. He received financial support for research activities from Genzyme-Sanofi, Celgene, Novartis, Mapi Pharma, V-WAVE Medical, and Protembis.

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Bergsland, N., Tavazzi, E., Schweser, F. et al. Targeting Iron Dyshomeostasis for Treatment of Neurodegenerative Disorders. CNS Drugs 33, 1073–1086 (2019). https://doi.org/10.1007/s40263-019-00668-6

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