TrkA-mediated endocytosis of p75-CTF prevents cholinergic neuron death upon γ-secretase inhibition
| Autor: | Lucía Chávez-Gutiérrez, Raquel Comaposada-Baró, María Luisa Franco, Marçal Vilar, Juan J Escribano-Saiz, Irmina García-Carpio |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Generalitat Valenciana, Fondation Recherche Alzheimer, Research Foundation - Flanders, Vilar, Marçal [0000-0002-9376-6544], Vilar, Marçal |
| Rok vydání: | 2021 |
| Předmět: |
Life Sciences & Biomedicine - Other Topics
0301 basic medicine C-JUN Health Toxicology and Mutagenesis Amino Acid Motifs Plant Science Tropomyosin receptor kinase A Ligands Receptor Nerve Growth Factor INTRAMEMBRANE PROTEOLYSIS 0302 clinical medicine Low-affinity nerve growth factor receptor Cycloheximide GENE-EXPRESSION Basal forebrain Cell Death Ecology Chemistry LINKED DIMERS Neurodegeneration Cholinergic Neurons Endocytosis Cell biology P75 NEUROTROPHIN RECEPTOR Life Sciences & Biomedicine Research Article Protein Binding endocrine system Programmed cell death BASAL FOREBRAIN NEURONS MAP Kinase Signaling System Notch signaling pathway Biochemistry Genetics and Molecular Biology (miscellaneous) 03 medical and health sciences Alzheimer Disease medicine Humans Protein Interaction Domains and Motifs Receptor trkA Cholinergic neuron Biology Science & Technology NERVE GROWTH-FACTOR medicine.disease P75(NTR) LIPID RAFTS 030104 developmental biology nervous system COGNITIVE DECLINE Proteolysis Cholinergic Amyloid Precursor Protein Secretases Protein Multimerization 030217 neurology & neurosurgery |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Life Science Alliance |
| ISSN: | 2017-8409 |
| Popis: | 20 páginas, 8 figuras γ-secretase inhibitors (GSI) were developed to reduce the generation of Aβ peptide to find new Alzheimer's disease treatments. Clinical trials on Alzheimer's disease patients, however, showed several side effects that worsened the cognitive symptoms of the treated patients. The observed side effects were partially attributed to Notch signaling. However, the effect on other γ-secretase substrates, such as the p75 neurotrophin receptor (p75NTR) has not been studied in detail. p75NTR is highly expressed in the basal forebrain cholinergic neurons (BFCNs) during all life. Here, we show that GSI treatment induces the oligomerization of p75CTF leading to the cell death of BFCNs, and that this event is dependent on TrkA activity. The oligomerization of p75CTF requires an intact cholesterol recognition sequence (CRAC) and the constitutive binding of TRAF6, which activates the JNK and p38 pathways. Remarkably, TrkA rescues from cell death by a mechanism involving the endocytosis of p75CTF. These results suggest that the inhibition of γ-secretase activity in aged patients, where the expression of TrkA in the BFCNs is already reduced, could accelerate cholinergic dysfunction and promote neurodegeneration. This study was supported by the Spanish Minister of Economy and Competitiveness grant SAF2017-84096-R and by the Generalitat Valenciana 2018-55 to M Vilar. I García-Carpio was supported by an Formación de Personal Investigador (FPI) pre-doctoral fellowship (BFU2013/42746-P) and a mobility grant (EEBB-I-15-10278) from the Spanish Minister of Economy and Competitiveness. This work was funded by the Stichting Alzheimer Onderzoek (S16013) and the Fonds voor Wetenschappelijk Onderzoek or Flanders Research Foundation (FWO) research project (G0B2519N) to L Chavez-Gutiérrez |
| Databáze: | OpenAIRE |
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