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Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome.

ABSTRACT: Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by severe intellectual disability and other symptoms including autism. Although caused by the silencing of a single gene, Fmr1 (fragile X mental retardation 1), the complexity of FXS pathogenesis is amplified because the encoded protein, FMRP, regulates the activity-dependent translation of numerous mRNAs. Although the mRNAs that associate with FMRP have been extensively studied, little is known regarding the proteins whose expression levels are altered, directly or indirectly, by loss of FMRP during brain development. Here we systematically measured protein expression in neocortical synaptic fractions from Fmr1 knockout (KO) and wild-type (WT) mice at both adolescent and adult stages. Although hundreds of proteins are up-regulated in the absence of FMRP in young mice, this up-regulation is largely diminished in adulthood. Up-regulated proteins included previously unidentified as well as known targets involved in synapse formation and function and brain development and others linked to intellectual disability and autism. Comparison with putative FMRP target mRNAs and autism susceptibility genes revealed substantial overlap, consistent with the idea that the autism endophenotype of FXS is due to a "multiple hit" effect of FMRP loss, particularly within the PSD95 interactome. Through studies of de novo protein synthesis in primary cortical neurons from KO and WT mice, we found that neurons lacking FMRP produce nascent proteins at higher rates, many of which are synaptic proteins and encoded by FMRP target mRNAs. Our results provide a greatly expanded view of protein changes in FXS and identify age-dependent effects of FMRP in shaping the neuronal proteome.

SUBMITTER: Tang B

PROVIDER: S-EPMC4553823 | biostudies-other | 2015 Aug

REPOSITORIES: biostudies-other

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Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome.

Tang Bin B Wang Tingting T Wan Huida H Han Li L Qin Xiaoyan X Zhang Yaoyang Y Wang Jian J Yu Chunlei C Berton Fulvia F Francesconi Walter W Yates John R JR Vanderklish Peter W PW Liao Lujian L

Proceedings of the National Academy of Sciences of the United States of America 20150811 34

Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder characterized by severe intellectual disability and other symptoms including autism. Although caused by the silencing of a single gene, Fmr1 (fragile X mental retardation 1), the complexity of FXS pathogenesis is amplified because the encoded protein, FMRP, regulates the activity-dependent translation of numerous mRNAs. Although the mRNAs that associate with FMRP have been extensively studied, little is known regarding the prote ...[more]

PMID: 26307763

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Project description:Importance:Findings from unbiased genetic studies have consistently implicated synaptic protein networks in schizophrenia, but the molecular pathologic features within these networks and their contribution to the synaptic and circuit deficits thought to underlie disease symptoms remain unknown. Objective:To determine whether protein levels are altered within synapses from the primary auditory cortex (A1) of individuals with schizophrenia and, if so, whether these differences are restricted to the synapse or occur throughout the gray matter. Design, Setting, and Participants:This paired case-control study included tissue samples from individuals with schizophrenia obtained from the Allegheny County Office of the Medical Examiner. An independent panel of health care professionals made consensus DSM-IV diagnoses. Each tissue sample from an individual with schizophrenia was matched by sex, age, and postmortem interval with 1 sample from an unaffected control individual. Targeted mass spectrometry was used to measure protein levels in A1 gray matter homogenate and synaptosome preparations. All experimenters were blinded to diagnosis. Mass spectrometry data were collected from September 26 through November 4, 2016, and analyzed from November 3, 2016, to July 15, 2019. Main Outcomes and Measures:Primary measures were homogenate and synaptosome protein levels and their coregulation network features. Hypotheses generated before data collection were (1) that levels of canonical postsynaptic proteins in A1 synaptosome preparations would differ between individuals with schizophrenia and controls and (2) that these differences would not be explained by changes in total A1 homogenate protein levels. Results:Synaptosome and homogenate protein levels were investigated in 48 individuals with a schizophrenia diagnosis and 48 controls (mean age in both groups, 48 years [range, 17-83 years]); each group included 35 males (73%) and 13 females (27%). Robust alterations (statistical cutoff set at an adjusted Limma P?<?.05) were observed in synaptosome levels of canonical mitochondrial and postsynaptic proteins that were highly coregulated and not readily explained by postmortem interval, antipsychotic drug treatment, synaptosome yield, or underlying alterations in homogenate protein levels. Conclusions and Relevance:These findings suggest a robust and highly coordinated rearrangement of the synaptic proteome. In line with unbiased genetic findings, alterations in synaptic levels of postsynaptic proteins were identified, providing a road map to identify the specific cells and circuits that are impaired in individuals with schizophrenia A1.

Dataset Information

Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome.

Publications

Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome.

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