Therapeutic potential of iron modulating drugs in a mouse model of multiple system atrophy.

Abstract

Multiple System Atrophy (MSA) is a rare neurodegenerative synucleinopathy which leads to severe disability followed by death within 6-9 years of symptom onset. There is compelling evidence suggesting that biological trace metals like iron and copper play an important role in synucleinopathies like Parkinson's disease and removing excess brain iron using chelators could slow down the disease progression. In human MSA, there is evidence of increased iron in affected brain regions, but role of iron and therapeutic efficacy of iron-lowering drugs in pre-clinical models of MSA have not been studied. We studied age-related changes in iron metabolism in different brain regions of the PLP-αsyn mice and tested whether iron-lowering drugs could alleviate disease phenotype in aged PLP-αsyn mice. Iron content, iron-ferritin association, ferritin protein levels and copper-ceruloplasmin association were measured in prefrontal cortex, putamen, substantia nigra and cerebellum of 3, 8, and 20-month-old PLP-αsyn and age-matched non-transgenic mice. Moreover, 12-month-old PLP-αsyn mice were administered deferiprone or ceruloplasmin or vehicle for 2 months. At the end of treatment period, motor testing and stereological analyses were performed. We found iron accumulation and perturbed iron-ferritin interaction in substantia nigra, putamen and cerebellum of aged PLP-αsyn mice. Furthermore, we found significant reduction in ceruloplasmin-bound copper in substantia nigra and cerebellum of the PLP-αsyn mice. Both deferiprone and ceruloplasmin prevented decline in motor performance in aged PLP-αsyn mice and were associated with higher neuronal survival and reduced density of α-synuclein aggregates in substantia nigra. This is the first study to report brain iron accumulation in a mouse model of MSA. Our results indicate that elevated iron in MSA mice may result from ceruloplasmin dysfunction and provide evidence that targeting iron in MSA could be a viable therapeutic option.

• Authors: Jay J Shukla, Nadia Stefanova, Ashley I Bush, Gawain McColl, David I Finkelstein, Erin J McAllum
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 159 Pg. 105509 (11 2021) ISSN: 1095-953X [Electronic] United States
• PMID: 34537326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Iron Chelating Agents
• SNCA protein, human
• alpha-Synuclein
• Deferiprone
• Copper
• Ferritins
• Iron
• Ceruloplasmin

Topics

• Animals
• Brain (drug effects, metabolism, pathology)
• Cerebellum (drug effects, metabolism, pathology)
• Ceruloplasmin (pharmacology)
• Copper (metabolism)
• Deferiprone (pharmacology)
• Disease Models, Animal
• Ferritins (drug effects, metabolism)
• Iron (metabolism)
• Iron Chelating Agents (pharmacology)
• Mice
• Mice, Transgenic
• Multiple System Atrophy (genetics, metabolism, pathology, physiopathology)
• Prefrontal Cortex (drug effects, metabolism, pathology)
• Putamen (drug effects, metabolism, pathology)
• Substantia Nigra (drug effects, metabolism, pathology)
• alpha-Synuclein (genetics)