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

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...

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Vydáno v:	Neuron (Cambridge, Mass.) Ročník 87; číslo 2; s. 382
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 15.07.2015
Témata:	ADAM Proteins - genetics ADAM Proteins - metabolism ADAM10 Protein Adolescent Adult Age Factors Amyloid beta-Protein Precursor - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - metabolism Animals Animals, Newborn Cells, Cultured Cerebral Cortex - cytology Child Female Fragile X Syndrome - genetics Fragile X Syndrome - pathology Gene Expression Regulation - genetics Green Fluorescent Proteins - genetics Green Fluorescent Proteins - metabolism Humans Male Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Inbred C57BL Mice, Transgenic Neurons - drug effects Neurons - metabolism Neurons - ultrastructure Synapses - pathology Time Factors Young Adult
ISSN:	1097-4199, 1097-4199
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4199 1097-4199
DOI:	10.1016/j.neuron.2015.06.032