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).
Autistic brains show the same FMRP imbalance as fragile X syndrome, suggesting shared treatment targets.
01Research in Context
What this study did
Scientists looked at brain tissue from 15 people who had autism.
They used special stains to see how much FMRP protein was in each cell.
FMRP is the protein missing in fragile X syndrome.
They checked both neurons and astrocytes across many brain areas.
What they found
Neurons in autistic brains had less FMRP than normal.
Astrocytes had more FMRP than they should.
This flip-flop pattern showed up in both cortex and deeper brain areas.
The same pattern happens in fragile X syndrome, but for different reasons.
How this fits with other research
Cioana et al. (2020) also studied autism brain tissue but looked at IGF-1 instead.
They found normal levels, showing not every protein is altered in autism.
Meuret et al. (2001) found another protein (NCAM-180) was low in autism brains too.
This suggests multiple molecular pathways may be disrupted.
Harada et al. (2011) found low GABA in living autistic people, which might connect to FMRP changes since FMRP helps regulate brain chemistry.
Why it matters
This tells us autism and fragile X may share some brain chemistry problems.
You can't test FMRP in living people yet, but knowing this pathway helps explain why some autistic clients respond to treatments developed for fragile X.
It also suggests astrocytes, not just neurons, matter in autism.
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02At a glance
03Original 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. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Immunocytochemistry reveals a deficit of fragile X mental retardation protein (FMRP) in neurons of cortical and subcortical brain structures but increased FMRP expression in astrocytes infiltrating gray and white matter. The detected shrinkage of FMRP-deficient neurons may provide a mechanistic explanation of reported neuronal structural and functional changes in autism. This study contributes to growing evidence of mechanistic commonalities between fragile X syndrome and autism spectrum disorder.
Autism research : official journal of the International Society for Autism Research, 2018 · doi:10.1002/aur.2003