The role of reduced expression of fragile X mental retardation protein in neurons and increased expression in astrocytes in idiopathic and syndromic autism (duplications 15q11.2-q13)

Jarek Wegiel, W. Ted Brown, Giuseppe La Fauci, Tatyana Adayev, Richard Kascsak, Regina Kascsak, Michael Flory, Wojciech Kaczmarski, Izabela Kuchna, Krzysztof Nowicki, Veronica Martinez-Cerdeno, Thomas Wisniewski, Jerzy Wegiel

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Abstract

Fragile X syndrome (FXS), caused by lack of fragile X mental retardation protein (FMRP), is associated with a high prevalence of autism. The deficit of FMRP reported in idiopathic autism suggests a mechanistic overlap between FXS and autism. The overall goal of this study is to detect neuropathological commonalities of FMRP deficits in the brains of people with idiopathic autism and with syndromic autism caused by dup15q11.2-q13 (dup15). This study tests the hypothesis based on our preliminary data that both idiopathic and syndromic autism are associated with brain region-specific deficits of neuronal FMRP and structural changes of the affected neurons. This immunocytochemical study revealed neuronal FMRP deficits and shrinkage of deficient neurons in the cerebral cortex, subcortical structures, and cerebellum in subjects with idiopathic and dup(15)/autism. Neuronal FMRP deficit coexists with surprising infiltration of the brains of autistic children and adults with FMRP-positive astrocytes known to be typical only for the fetal and short postnatal periods. In the examined autistic subjects, these astrocytes selectively infiltrate the border between white and gray matter in the cerebral and cerebellar cortex, the molecular layer of the cortex, part of the amygdala and thalamus, central cerebellar white matter, and dentate nucleus. Astrocyte pathology results in an additional local loss of FMRP in neurons and their shrinkage. Neuronal deficit of FMRP and shrinkage of affected neurons in structures free of FMRP-positive astrocytes and regions infiltrated with FMRP-expressing astrocytes appear to reflect mechanistic, neuropathological, and functional commonalities of FMRP abnormalities in FXS and autism spectrum disorder. Autism Res 2018, 11: 1316–1331.

Original languageEnglish (US)
Pages (from-to)1316-1331
Number of pages16
JournalAutism Research
Volume11
Issue number10
DOIs
StatePublished - Oct 1 2018

Keywords

  • astrocyte
  • duplication 15q11.2-q13/autism
  • fragile X mental retardation protein
  • idiopathic autism
  • neuron

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Genetics(clinical)

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    Wegiel, J., Brown, W. T., La Fauci, G., Adayev, T., Kascsak, R., Kascsak, R., Flory, M., Kaczmarski, W., Kuchna, I., Nowicki, K., Martinez-Cerdeno, V., Wisniewski, T., & Wegiel, J. (2018). The role of reduced expression of fragile X mental retardation protein in neurons and increased expression in astrocytes in idiopathic and syndromic autism (duplications 15q11.2-q13). Autism Research, 11(10), 1316-1331. https://doi.org/10.1002/aur.2003