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 language | English (US) |
|---|---|
| Pages (from-to) | 382-399 |
| Number of pages | 18 |
| Journal | Neuron |
| Volume | 87 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jul 15 2015 |
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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 journal › Article
}
TY - JOUR
T1 - Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome
AU - Pasciuto, Emanuela
AU - Ahmed, Tariq
AU - Wahle, Tina
AU - Gardoni, Fabrizio
AU - D'Andrea, Laura
AU - Pacini, Laura
AU - Jacquemont, Sébastien
AU - Tassone, Flora
AU - Balschun, Detlef
AU - Dotti, Carlos G.
AU - Callaerts-Vegh, Zsuzsanna
AU - D'Hooge, Rudi
AU - Müller, Ulrike C.
AU - Di Luca, Monica
AU - De Strooper, Bart
AU - Bagni, Claudia
PY - 2015/7/15
Y1 - 2015/7/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84937432830&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937432830&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2015.06.032
DO - 10.1016/j.neuron.2015.06.032
M3 - Article
C2 - 26182420
AN - SCOPUS:84937432830
VL - 87
SP - 382
EP - 399
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 2
ER -