Microglial cell activation and senescence are characteristic of the pathology FXTAS

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Abstract

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene. Expansions of more than 200 CGG repeats give rise to fragile X syndrome, the most common inherited form of cognitive impairment. Fragile X-associated tremor/ataxia syndrome is characterized by cerebellar tremor and ataxia, and the presence of ubiquitin-positive inclusions in neurons and astrocytes. It has been previously suggested that fragile X-associated tremor/ataxia syndrome is associated with an inflammatory state based on signs of oxidative stress–mediated damage and iron deposition. Objective: Determine whether the pathology of fragile X-associated tremor/ataxia syndrome involves microglial activation and an inflammatory state. Methods: Using ionized calcium binding adaptor molecule 1 and cluster differentiation 68 antibodies to label microglia, we examined the number and state of activation of microglial cells in the putamen of 13 fragile X-associated tremor/ataxia syndrome and 9 control postmortem cases. Results: Nearly half of fragile X-associated tremor/ataxia syndrome cases (6 of 13) presented with dystrophic senescent microglial cells. In the remaining fragile X-associated tremor/ataxia syndrome cases (7 of 13), the number of microglial cells and their activation state were increased compared to controls. Conclusions: The presence of senescent microglial cells in half of fragile X-associated tremor/ataxia syndrome cases suggests that this indicator could be used, together with the presence of intranuclear inclusions and the presence of iron deposits, as a biomarker to aid in the postmortem diagnosis of fragile X-associated tremor/ataxia syndrome. An increased number and activation indicate that microglial cells play a role in the inflammatory state present in the fragile X-associated tremor/ataxia syndrome brain. Anti-inflammatory treatment of patients with fragile X-associated tremor/ataxia syndrome may be indicated to slow neurodegeneration.

Original languageEnglish (US)
Pages (from-to)1887-1894
Number of pages8
JournalMovement Disorders
Volume33
Issue number12
DOIs
StatePublished - Dec 1 2018

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Cell Aging
Pathology
Fragile X Tremor Ataxia Syndrome
Iron
Intranuclear Inclusion Bodies
Fragile X Syndrome
Cerebellar Ataxia
Putamen
Microglia
Tremor
Ubiquitin
Astrocytes
Neurodegenerative Diseases
Anti-Inflammatory Agents
Cell Count
Biomarkers
Alleles
Calcium
Neurons

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Microglial cell activation and senescence are characteristic of the pathology FXTAS. / Martinez-Cerdeno, Veronica; Hong, Tiffany; Amina, Sarwat; Lechpammer, Mirna; Ariza, Jeanelle; Tassone, Flora; Noctor, Stephen C; Hagerman, Paul J; Hagerman, Randi J.

In: Movement Disorders, Vol. 33, No. 12, 01.12.2018, p. 1887-1894.

Research output: Contribution to journalArticle

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title = "Microglial cell activation and senescence are characteristic of the pathology FXTAS",
abstract = "Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene. Expansions of more than 200 CGG repeats give rise to fragile X syndrome, the most common inherited form of cognitive impairment. Fragile X-associated tremor/ataxia syndrome is characterized by cerebellar tremor and ataxia, and the presence of ubiquitin-positive inclusions in neurons and astrocytes. It has been previously suggested that fragile X-associated tremor/ataxia syndrome is associated with an inflammatory state based on signs of oxidative stress–mediated damage and iron deposition. Objective: Determine whether the pathology of fragile X-associated tremor/ataxia syndrome involves microglial activation and an inflammatory state. Methods: Using ionized calcium binding adaptor molecule 1 and cluster differentiation 68 antibodies to label microglia, we examined the number and state of activation of microglial cells in the putamen of 13 fragile X-associated tremor/ataxia syndrome and 9 control postmortem cases. Results: Nearly half of fragile X-associated tremor/ataxia syndrome cases (6 of 13) presented with dystrophic senescent microglial cells. In the remaining fragile X-associated tremor/ataxia syndrome cases (7 of 13), the number of microglial cells and their activation state were increased compared to controls. Conclusions: The presence of senescent microglial cells in half of fragile X-associated tremor/ataxia syndrome cases suggests that this indicator could be used, together with the presence of intranuclear inclusions and the presence of iron deposits, as a biomarker to aid in the postmortem diagnosis of fragile X-associated tremor/ataxia syndrome. An increased number and activation indicate that microglial cells play a role in the inflammatory state present in the fragile X-associated tremor/ataxia syndrome brain. Anti-inflammatory treatment of patients with fragile X-associated tremor/ataxia syndrome may be indicated to slow neurodegeneration.",
author = "Veronica Martinez-Cerdeno and Tiffany Hong and Sarwat Amina and Mirna Lechpammer and Jeanelle Ariza and Flora Tassone and Noctor, {Stephen C} and Hagerman, {Paul J} and Hagerman, {Randi J}",
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T1 - Microglial cell activation and senescence are characteristic of the pathology FXTAS

AU - Martinez-Cerdeno, Veronica

AU - Hong, Tiffany

AU - Amina, Sarwat

AU - Lechpammer, Mirna

AU - Ariza, Jeanelle

AU - Tassone, Flora

AU - Noctor, Stephen C

AU - Hagerman, Paul J

AU - Hagerman, Randi J

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene. Expansions of more than 200 CGG repeats give rise to fragile X syndrome, the most common inherited form of cognitive impairment. Fragile X-associated tremor/ataxia syndrome is characterized by cerebellar tremor and ataxia, and the presence of ubiquitin-positive inclusions in neurons and astrocytes. It has been previously suggested that fragile X-associated tremor/ataxia syndrome is associated with an inflammatory state based on signs of oxidative stress–mediated damage and iron deposition. Objective: Determine whether the pathology of fragile X-associated tremor/ataxia syndrome involves microglial activation and an inflammatory state. Methods: Using ionized calcium binding adaptor molecule 1 and cluster differentiation 68 antibodies to label microglia, we examined the number and state of activation of microglial cells in the putamen of 13 fragile X-associated tremor/ataxia syndrome and 9 control postmortem cases. Results: Nearly half of fragile X-associated tremor/ataxia syndrome cases (6 of 13) presented with dystrophic senescent microglial cells. In the remaining fragile X-associated tremor/ataxia syndrome cases (7 of 13), the number of microglial cells and their activation state were increased compared to controls. Conclusions: The presence of senescent microglial cells in half of fragile X-associated tremor/ataxia syndrome cases suggests that this indicator could be used, together with the presence of intranuclear inclusions and the presence of iron deposits, as a biomarker to aid in the postmortem diagnosis of fragile X-associated tremor/ataxia syndrome. An increased number and activation indicate that microglial cells play a role in the inflammatory state present in the fragile X-associated tremor/ataxia syndrome brain. Anti-inflammatory treatment of patients with fragile X-associated tremor/ataxia syndrome may be indicated to slow neurodegeneration.

AB - Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene. Expansions of more than 200 CGG repeats give rise to fragile X syndrome, the most common inherited form of cognitive impairment. Fragile X-associated tremor/ataxia syndrome is characterized by cerebellar tremor and ataxia, and the presence of ubiquitin-positive inclusions in neurons and astrocytes. It has been previously suggested that fragile X-associated tremor/ataxia syndrome is associated with an inflammatory state based on signs of oxidative stress–mediated damage and iron deposition. Objective: Determine whether the pathology of fragile X-associated tremor/ataxia syndrome involves microglial activation and an inflammatory state. Methods: Using ionized calcium binding adaptor molecule 1 and cluster differentiation 68 antibodies to label microglia, we examined the number and state of activation of microglial cells in the putamen of 13 fragile X-associated tremor/ataxia syndrome and 9 control postmortem cases. Results: Nearly half of fragile X-associated tremor/ataxia syndrome cases (6 of 13) presented with dystrophic senescent microglial cells. In the remaining fragile X-associated tremor/ataxia syndrome cases (7 of 13), the number of microglial cells and their activation state were increased compared to controls. Conclusions: The presence of senescent microglial cells in half of fragile X-associated tremor/ataxia syndrome cases suggests that this indicator could be used, together with the presence of intranuclear inclusions and the presence of iron deposits, as a biomarker to aid in the postmortem diagnosis of fragile X-associated tremor/ataxia syndrome. An increased number and activation indicate that microglial cells play a role in the inflammatory state present in the fragile X-associated tremor/ataxia syndrome brain. Anti-inflammatory treatment of patients with fragile X-associated tremor/ataxia syndrome may be indicated to slow neurodegeneration.

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