Elsevier

Neurobiology of Disease

Volume 159, November 2021, 105509
Neurobiology of Disease

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

https://doi.org/10.1016/j.nbd.2021.105509Get rights and content
Under a Creative Commons license
open access

Highlights

  • Region-specific brain iron accumulation in a mouse model of Multiple System Atrophy.

  • Aged PLP-αsyn mice accumulate iron in substantia nigra, putamen and cerebellum.

  • Iron accumulation is accompanied by reduced iron-ferritin association.

  • Ceruloplasmin dysfunction may cause brain iron accumulation in PLP-αsyn mice.

  • Deferiprone and ceruloplasmin therapy alleviated disease phenotype in PLP-αsyn mice.

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.

Keywords

Multiple system atrophy
α-Synuclein
Iron
Deferiprone
Synucleinopathy
Ceruloplasmin

Cited by (0)

1

Present address: Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.