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

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-alpha syn mice and tested whether iron-lowering drugs could alleviate disease phenotype in aged PLP-alpha syn 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-alpha syn and age-matched non-transgenic mice. Moreover, 12-month-old PLP-alpha syn 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-alpha syn mice. Furthermore, we found significant reduction in ceruloplasmin-bound copper in substantia nigra and cerebellum of the PLP-alpha syn mice. Both deferiprone and ceruloplasmin prevented decline in motor performance in aged PLP-alpha syn mice and were associated with higher neuronal survival and reduced density of alpha-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.

Automated summary

This study found changes in iron metabolism in different brain regions of aged PLP-alpha syn mice and tested the efficacy of iron-lowering drugs in alleviating disease phenotype in these mice. The results indicated iron accumulation and perturbed iron-ferritin interaction in the substantia nigra, putamen, and cerebellum of aged PLP-alpha syn mice. Additionally, targeting iron in MSA could be a viable therapeutic option as shown by improvements in motor performance and neuronal survival in the study.