Details

Autor(en) / Beteiligte

• Schöbel, Susanne
• Neumann, Stephanie
• Hertweck, Maren
• Dislich, Bastian
• Kuhn, Peer-Hendrik
• Kremmer, Elisabeth
• Seed, Brian
• Baumeister, Ralf
• Haass, Christian
• Lichtenthaler, Stefan F.

Titel

A Novel Sorting Nexin Modulates Endocytic Trafficking and α-Secretase Cleavage of the Amyloid Precursor Protein

Ist Teil von

• The Journal of biological chemistry, 2008-05, Vol.283 (21), p.14257-14268

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2008

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases α- and β-secretase is a key regulatory event in the generation of the Alzheimer disease amyloid β peptide (Aβ). β-Secretase catalyzes the first step in Aβ generation, whereas α-secretase cleaves within the Aβ domain, prevents Aβ generation, and generates a secreted form of APP with neuroprotective properties. At present, little is known about the cellular mechanisms that control APP α-secretase cleavage and Aβ generation. To explore the contributory pathways, we carried out an expression cloning screen. We identified a novel member of the sorting nexin (SNX) family of endosomal trafficking proteins, called SNX33, as a new activator of APP α-secretase cleavage. SNX33 is a homolog of SNX9 and was found to be a ubiquitously expressed phosphoprotein. Exogenous expression of SNX33 in cultured cells increased APP α-secretase cleavage 4-fold but surprisingly had little effect on β-secretase cleavage. This effect was similar to the expression of the dominant negative dynamin-1 mutant K44A. SNX33 bound the endocytic GTPase dynamin and reduced the rate of APP endocytosis in a dynamin-dependent manner. This led to an increase of APP at the plasma membrane, where α-secretase cleavage mostly occurs. In summary, our study identifies SNX33 as a new endocytic protein, which modulates APP endocytosis and APP α-secretase cleavage, and demonstrates that the rate of APP endocytosis is a major control factor for APP α-secretase cleavage.