Deficiency of Aph1B/C-gamma-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment.
Regulated intramembrane proteolysis by gamma-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different gamma-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated the involvement of the Aph1A-gamma-secretase complex in Notch signaling, but no specific function could be assigned to Aph1B/C-gamma-secretase. We demonstrate here that the Aph1B/C-gamma-secretase complex is expressed in brain areas relevant to schizophrenia pathogenesis and that Aph1B/C deficiency causes pharmacological and behavioral abnormalities that can be reversed by antipsychotic drugs. At the molecular level we find accumulation of Nrg1 fragments in the brain of Aph1BC(-/-) mice. Our observations gain clinical relevance by the demonstration that a Val-to-Leu mutation in the Nrg1 transmembrane domain, associated with increased risk for schizophrenia, affects gamma-secretase cleavage of Nrg1. This finding suggests that dysregulation of intramembrane proteolysis of Nrg1 could increase risk for schizophrenia and related disorders.
Dejaegere
T
T
Department of Molecular and Developmental Genetics, Vlaams Instituut voor Biotechnologie, 3000 Leuven, Belgium.
Serneels
L
L
Schäfer
M K
MK
Van Biervliet
J
J
Horré
K
K
Depboylu
C
C
Alvarez-Fischer
D
D
Herreman
A
A
Willem
M
M
Haass
C
C
Höglinger
G U
GU
D'Hooge
R
R
De Strooper
B
B
D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010450:Endopeptidases / Q000172:deficiency*; D020233:Gait Disorders, Neurologic / Q000209:etiology*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense / Q000502:physiology; D020890:Neuregulin-1 / Q000378:metabolism*; D021122:Protein Subunits / Q000172:deficiency*; D012559:Schizophrenia / Q000209:etiology
D014150:Antipsychotic Agents; D008565:Membrane Proteins; D020890:Neuregulin-1; D021122:Protein Subunits; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; C498196:Aph1C protein, mouse; C498195:Aph1b protein, mouse