Dataset Information

Unbalanced protein expression contributes to pathology in Fragile X Syndrome

ABSTRACT: Dysregulated protein synthesis is a core pathogenic mechanism in Fragile X Syndrome (FX). The mGluR Theory of FX predicts that pathological synaptic changes arise from the excessive translation of mRNAs downstream of mGlu1/5 activation. Here, we use a combination of CA1 pyramidal neuron-specific Translating Ribosome Affinity Purification and RNA-seq (TRAP-seq) and proteomics to identify the overtranslating mRNAs supporting exaggerated mGlu1/5 -induced long-term synaptic depression (mGluR-LTD) in the FX mouse model (Fmr1-/y). Our results identify a robust translation of ribosomal proteins (RPs) upon mGlu1/5 stimulation that coincides with a reduced translation of long mRNAs encoding synaptic proteins. These changes are mimicked and occluded in Fmr1-/y neurons. In addition, proteomics analyses identify increased degradation of multiple proteins at hippocampal synapses, many of which are underexpressed at steady-state.

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Miguel A. Gonzalez-Lozano

LAB HEAD: Ka Wan Li

PROVIDER: PXD031932 | Pride | 2022-06-16

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20170203_P2_30ug_Swath_Edinburgh_A3.wiff	Wiff
	20170203_P2_30ug_Swath_Edinburgh_A3.wiff.scan	Wiff
	20170203_P2_30ug_Swath_Edinburgh_A4.wiff	Wiff
	20170203_P2_30ug_Swath_Edinburgh_A4.wiff.scan	Wiff
	20170203_P2_30ug_Swath_Edinburgh_A5.wiff	Wiff

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Publications

Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome.

Seo Sang S SS Louros Susana R SR Anstey Natasha N Gonzalez-Lozano Miguel A MA Harper Callista B CB Verity Nicholas C NC Dando Owen O Thomson Sophie R SR Darnell Jennifer C JC Kind Peter C PC Li Ka Wan KW Osterweil Emily K EK

Nature communications 20220610 1

Dysregulated protein synthesis is a core pathogenic mechanism in Fragile X Syndrome (FX). The mGluR Theory of FX predicts that pathological synaptic changes arise from the excessive translation of mRNAs downstream of mGlu1/5 activation. Here, we use a combination of CA1 pyramidal neuron-specific TRAP-seq and proteomics to identify the overtranslating mRNAs supporting exaggerated mGlu1/5 -induced long-term synaptic depression (mGluR-LTD) in the FX mouse model (Fmr1-/y</ ...[more]

PMID: 35688821

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