Microglial cell activation and senescence are characteristic of the pathology FXTAS

• Published in: Movement disorders 2018-12, Vol.33 (12), p.1887-1894
• Main Authors: Martínez Cerdeño, Verónica, Hong, Tiffany, Amina, Sarwat, Lechpammer, Mirna, Ariza, Jeanelle, Tassone, Flora, Noctor, Stephen C., Hagerman, Paul, Hagerman, Randi
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Astrocytes; Astrocytes - pathology; Ataxia; Ataxia - pathology; Ataxia - therapy; Autopsy; Brain - pathology; Brain - physiopathology; Calcium; Cell activation; Cerebellum; Cognitive ability; Female; FMR1 protein; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - therapeutic use; Fragile X syndrome; Fragile X Syndrome - pathology; Fragile X Syndrome - therapy; Humans; Inclusion bodies; Inflammation; Intellectual disabilities; Iron; Male; Microglia; Microglial cells; Middle Aged; Movement disorders; Movement Disorders - genetics; Movement Disorders - pathology; Movement Disorders - therapy; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - pathology; Neurodegenerative Diseases - therapy; Neurons - pathology; Oxidative stress; Putamen; Senescence; Tremor; Tremor - pathology; Tremor - physiopathology; Tremor - therapy; Ubiquitin
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.27553

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. © 2018 International Parkinson and Movement Disorder Society