Iron accumulation and dysregulation in the putamen in fragile X associated tremor/ataxia syndrome

Abstract

Background

Fragile X-associated tremor/ataxia Syndrome (FXTAS) is an adult-onset disorder associated with premutation alleles of the FMR1 gene. The disorder is characterized by progressive action tremor, gait ataxia, and cognitive decline. FXTAS pathology includes dystrophic white matter and intranuclear inclusions in neurons and astrocytes. We previously demonstrated that the transport of iron into the brain is altered in FXTAS; therefore, we also expect an alteration of iron metabolism in brain areas related to motor control. Iron is essential for cell metabolism, but uncomplexed iron leads to oxidative stress and contributes to the development of neurodegenerative diseases.

Objectives

We investigated a potential iron modification in the striatum, the structure that participates in motor learning and performance, in FXTAS.

Methods

We used samples of putamen obtained from 9 FXTAS and 9 control cases to study iron localization using Perl’s method, and iron-binding proteins using immunostaining.

Results

We found increased iron deposition in neuronal and glial cells, which accumulate iron, in the putamen in FXTAS. We also found a generalized decreased of the amount of the iron-binding proteins, transferrin and ceruloplasmin, in the putamen, and decreased numbers of neurons and glial cells that contained ceruloplasmin. However, we found increased levels of iron, transferrin, and ceruloplasmin in microglial cells, indicating the attempt by the immune system to remove the excess iron.

Conclusions

Overall, there is a deficit in proteins that eliminate extra iron from the cells with the concomitant increased in the deposit of cellular iron.