Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

Emanuela Pasciuto, Tariq Ahmed, Tina Wahle, Fabrizio Gardoni, Laura D'Andrea, Laura Pacini, Sébastien Jacquemont, Flora Tassone, Detlef Balschun, Carlos G. Dotti, Zsuzsanna Callaerts-Vegh, Rudi D'Hooge, Ulrike C. Müller, Monica Di Luca, Bart De Strooper, Claudia Bagni

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes. Pasciuto etal. show that dual dysregulation of APP and ADAM10, during a critical period of postnatal development, leads to overproduction of sAPPα. Modulation of ADAM10 activity re-establishes physiological sAPPα levels and ultimately ameliorates FXS molecular, synaptic, and behavioral deficits.

Original languageEnglish
Pages (from-to)382-399
Number of pages18
JournalNeuron
Volume87
Issue number2
DOIs
Publication statusPublished - 15 Jul 2015
Externally publishedYes

Fingerprint

Fragile X Syndrome
Amyloid beta-Protein Precursor
Synapses
Fragile X Mental Retardation Protein
Amyloid Precursor Protein Secretases
Intellectual Disability
Alzheimer Disease
Spine
Phosphotransferases
Down-Regulation
Fibroblasts
RNA
Phenotype
Mutation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome. / Pasciuto, Emanuela; Ahmed, Tariq; Wahle, Tina; Gardoni, Fabrizio; D'Andrea, Laura; Pacini, Laura; Jacquemont, Sébastien; Tassone, Flora; Balschun, Detlef; Dotti, Carlos G.; Callaerts-Vegh, Zsuzsanna; D'Hooge, Rudi; Müller, Ulrike C.; Di Luca, Monica; De Strooper, Bart; Bagni, Claudia.

In: Neuron, Vol. 87, No. 2, 15.07.2015, p. 382-399.

Research output: Contribution to journalArticle

Pasciuto, E, Ahmed, T, Wahle, T, Gardoni, F, D'Andrea, L, Pacini, L, Jacquemont, S, Tassone, F, Balschun, D, Dotti, CG, Callaerts-Vegh, Z, D'Hooge, R, Müller, UC, Di Luca, M, De Strooper, B & Bagni, C 2015, 'Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome', Neuron, vol. 87, no. 2, pp. 382-399. https://doi.org/10.1016/j.neuron.2015.06.032
Pasciuto, Emanuela ; Ahmed, Tariq ; Wahle, Tina ; Gardoni, Fabrizio ; D'Andrea, Laura ; Pacini, Laura ; Jacquemont, Sébastien ; Tassone, Flora ; Balschun, Detlef ; Dotti, Carlos G. ; Callaerts-Vegh, Zsuzsanna ; D'Hooge, Rudi ; Müller, Ulrike C. ; Di Luca, Monica ; De Strooper, Bart ; Bagni, Claudia. / Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome. In: Neuron. 2015 ; Vol. 87, No. 2. pp. 382-399.
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