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

Jeanelle Ariza, Hailee Rogers, Anna Hartvigsen, Melissa Snell, Michael Dill, Derek Judd, Paul J Hagerman, Veronica Martinez-Cerdeno

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: Fragile X-associated tremor/ataxia syndrome is an adult-onset disorder associated with premutation alleles of the FMR1 gene. This disorder is characterized by progressive action tremor, gait ataxia, and cognitive decline. Fragile X-associated tremor/ataxia syndrome 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 fragile X-associated tremor/ataxia syndrome; 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. We investigated a potential iron modification in the putamen - a structure that participates in motor learning and performance - in fragile X-associated tremor/ataxia syndrome. Methods: We used samples of putamen obtained from 9 fragile X-associated tremor/ataxia syndrome 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 in the putamen in fragile X-associated tremor/ataxia syndrome. We also found a generalized decrease in the amount of the iron-binding proteins transferrin and ceruloplasmin, and decreased number of neurons and glial cells that contained ceruloplasmin. However, we found increased levels of iron, transferrin, and ceruloplasmin in microglial cells, indicating an attempt by the immune system to remove the excess iron. Conclusions: Overall, found a deficit in proteins that eliminate extra iron from the cells with a concomitant increase in the deposit of cellular iron in the putamen in Fragile X-associated tremor/ataxia syndrome.

Original languageEnglish (US)
JournalMovement Disorders
DOIs
StateAccepted/In press - 2017

Fingerprint

Putamen
Iron
Ceruloplasmin
Iron-Binding Proteins
Transferrin
Neuroglia
Fragile X Tremor Ataxia Syndrome
Gait Ataxia
Neurons
Intranuclear Inclusion Bodies
Brain
Tremor
Astrocytes
Neurodegenerative Diseases
Case-Control Studies
Immune System
Oxidative Stress
Alleles
Learning
Pathology

Keywords

  • CGG
  • Dementia
  • Fragile X
  • FXTAS
  • Motor disorder
  • Neurodegeneration
  • Repeat-expansion disorder

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Iron accumulation and dysregulation in the putamen in fragile X-associated tremor/ataxia syndrome. / Ariza, Jeanelle; Rogers, Hailee; Hartvigsen, Anna; Snell, Melissa; Dill, Michael; Judd, Derek; Hagerman, Paul J; Martinez-Cerdeno, Veronica.

In: Movement Disorders, 2017.

Research output: Contribution to journalArticle

Ariza, Jeanelle ; Rogers, Hailee ; Hartvigsen, Anna ; Snell, Melissa ; Dill, Michael ; Judd, Derek ; Hagerman, Paul J ; Martinez-Cerdeno, Veronica. / Iron accumulation and dysregulation in the putamen in fragile X-associated tremor/ataxia syndrome. In: Movement Disorders. 2017.
@article{ba315d23aba041169cbe0cbf96cd1619,
title = "Iron accumulation and dysregulation in the putamen in fragile X-associated tremor/ataxia syndrome",
abstract = "Background: Fragile X-associated tremor/ataxia syndrome is an adult-onset disorder associated with premutation alleles of the FMR1 gene. This disorder is characterized by progressive action tremor, gait ataxia, and cognitive decline. Fragile X-associated tremor/ataxia syndrome 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 fragile X-associated tremor/ataxia syndrome; 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. We investigated a potential iron modification in the putamen - a structure that participates in motor learning and performance - in fragile X-associated tremor/ataxia syndrome. Methods: We used samples of putamen obtained from 9 fragile X-associated tremor/ataxia syndrome 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 in the putamen in fragile X-associated tremor/ataxia syndrome. We also found a generalized decrease in the amount of the iron-binding proteins transferrin and ceruloplasmin, and decreased number of neurons and glial cells that contained ceruloplasmin. However, we found increased levels of iron, transferrin, and ceruloplasmin in microglial cells, indicating an attempt by the immune system to remove the excess iron. Conclusions: Overall, found a deficit in proteins that eliminate extra iron from the cells with a concomitant increase in the deposit of cellular iron in the putamen in Fragile X-associated tremor/ataxia syndrome.",
keywords = "CGG, Dementia, Fragile X, FXTAS, Motor disorder, Neurodegeneration, Repeat-expansion disorder",
author = "Jeanelle Ariza and Hailee Rogers and Anna Hartvigsen and Melissa Snell and Michael Dill and Derek Judd and Hagerman, {Paul J} and Veronica Martinez-Cerdeno",
year = "2017",
doi = "10.1002/mds.26902",
language = "English (US)",
journal = "Movement Disorders",
issn = "0885-3185",
publisher = "John Wiley and Sons Inc.",

}

TY - JOUR

T1 - Iron accumulation and dysregulation in the putamen in fragile X-associated tremor/ataxia syndrome

AU - Ariza, Jeanelle

AU - Rogers, Hailee

AU - Hartvigsen, Anna

AU - Snell, Melissa

AU - Dill, Michael

AU - Judd, Derek

AU - Hagerman, Paul J

AU - Martinez-Cerdeno, Veronica

PY - 2017

Y1 - 2017

N2 - Background: Fragile X-associated tremor/ataxia syndrome is an adult-onset disorder associated with premutation alleles of the FMR1 gene. This disorder is characterized by progressive action tremor, gait ataxia, and cognitive decline. Fragile X-associated tremor/ataxia syndrome 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 fragile X-associated tremor/ataxia syndrome; 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. We investigated a potential iron modification in the putamen - a structure that participates in motor learning and performance - in fragile X-associated tremor/ataxia syndrome. Methods: We used samples of putamen obtained from 9 fragile X-associated tremor/ataxia syndrome 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 in the putamen in fragile X-associated tremor/ataxia syndrome. We also found a generalized decrease in the amount of the iron-binding proteins transferrin and ceruloplasmin, and decreased number of neurons and glial cells that contained ceruloplasmin. However, we found increased levels of iron, transferrin, and ceruloplasmin in microglial cells, indicating an attempt by the immune system to remove the excess iron. Conclusions: Overall, found a deficit in proteins that eliminate extra iron from the cells with a concomitant increase in the deposit of cellular iron in the putamen in Fragile X-associated tremor/ataxia syndrome.

AB - Background: Fragile X-associated tremor/ataxia syndrome is an adult-onset disorder associated with premutation alleles of the FMR1 gene. This disorder is characterized by progressive action tremor, gait ataxia, and cognitive decline. Fragile X-associated tremor/ataxia syndrome 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 fragile X-associated tremor/ataxia syndrome; 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. We investigated a potential iron modification in the putamen - a structure that participates in motor learning and performance - in fragile X-associated tremor/ataxia syndrome. Methods: We used samples of putamen obtained from 9 fragile X-associated tremor/ataxia syndrome 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 in the putamen in fragile X-associated tremor/ataxia syndrome. We also found a generalized decrease in the amount of the iron-binding proteins transferrin and ceruloplasmin, and decreased number of neurons and glial cells that contained ceruloplasmin. However, we found increased levels of iron, transferrin, and ceruloplasmin in microglial cells, indicating an attempt by the immune system to remove the excess iron. Conclusions: Overall, found a deficit in proteins that eliminate extra iron from the cells with a concomitant increase in the deposit of cellular iron in the putamen in Fragile X-associated tremor/ataxia syndrome.

KW - CGG

KW - Dementia

KW - Fragile X

KW - FXTAS

KW - Motor disorder

KW - Neurodegeneration

KW - Repeat-expansion disorder

UR - http://www.scopus.com/inward/record.url?scp=85013667606&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85013667606&partnerID=8YFLogxK

U2 - 10.1002/mds.26902

DO - 10.1002/mds.26902

M3 - Article

C2 - 28233916

AN - SCOPUS:85013667606

JO - Movement Disorders

JF - Movement Disorders

SN - 0885-3185

ER -