AraC interacts with p75NTR transmembrane domain to induce cell death of mature neurons

Vanessa Lopes-Rodrigues; Pia Boxy; Eunice Sim; Dong Ik Park; Michael Habeck; Josep Carbonell; Annika Andersson; Diana Fernández-Suárez; Poul Nissen; Anders Nykjær; Lilian Kisiswa

doi:10.1038/s41419-023-05979-7

AraC interacts with p75^NTR transmembrane domain to induce cell death of mature neurons

Vanessa Lopes-Rodrigues, Pia Boxy, Eunice Sim, Dong Ik Park, Michael Habeck, Josep Carbonell, Annika Andersson, Diana Fernández-Suárez, Poul Nissen, Anders Nykjær, Lilian Kisiswa^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Cytosine arabinoside (AraC) is one of the main therapeutic treatments for several types of cancer, including acute myeloid leukaemia. However, after a high-dose AraC chemotherapy regime, patients develop severe neurotoxicity and cell death in the central nervous system leading to cerebellar ataxia, dysarthria, nystagmus, somnolence and drowsiness. AraC induces apoptosis in dividing cells. However, the mechanism by which it leads to neurite degeneration and cell death in mature neurons remains unclear. We hypothesise that the upregulation of the death receptor p75^NTR is responsible for AraC-mediated neurodegeneration and cell death in leukaemia patients undergoing AraC treatment. To determine the role of AraC-p75^NTR signalling in the cell death of mature neurons, we used mature cerebellar granule neurons’ primary cultures from p75^NTR knockout and p75 ^NTRCys259 mice. Evaluation of neurite degeneration, cell death and p75^NTR signalling was done by immunohistochemistry and immunoblotting. To assess the interaction between AraC and p75^NTR, we performed cellular thermal shift and AraTM assays as well as Homo-FRET anisotropy imaging. We show that AraC induces neurite degeneration and programmed cell death of mature cerebellar granule neurons in a p75^NTR-dependent manner. Mechanistically, Proline 252 and Cysteine 256 residues facilitate AraC interaction with the transmembrane domain of p75^NTR resulting in uncoupling of p75^NTR from the NFκB survival pathway. This, in turn, exacerbates the activation of the cell death/JNK pathway by recruitment of TRAF6 to p75^NTR. Our findings identify p75^NTR as a novel molecular target to develop treatments for counteract AraC-mediated cell death of mature neurons.

Original language	English
Article number	440
Journal	Cell Death and Disease
Volume	14
Issue	7
Number of pages	13
ISSN	2041-4889
DOIs	https://doi.org/10.1038/s41419-023-05979-7
Publication status	Published - Jul 2023

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@article{f0e1344e386b46cda6800da1c8023c20,

title = "AraC interacts with p75NTR transmembrane domain to induce cell death of mature neurons",

abstract = "Cytosine arabinoside (AraC) is one of the main therapeutic treatments for several types of cancer, including acute myeloid leukaemia. However, after a high-dose AraC chemotherapy regime, patients develop severe neurotoxicity and cell death in the central nervous system leading to cerebellar ataxia, dysarthria, nystagmus, somnolence and drowsiness. AraC induces apoptosis in dividing cells. However, the mechanism by which it leads to neurite degeneration and cell death in mature neurons remains unclear. We hypothesise that the upregulation of the death receptor p75NTR is responsible for AraC-mediated neurodegeneration and cell death in leukaemia patients undergoing AraC treatment. To determine the role of AraC-p75NTR signalling in the cell death of mature neurons, we used mature cerebellar granule neurons{\textquoteright} primary cultures from p75NTR knockout and p75 NTRCys259 mice. Evaluation of neurite degeneration, cell death and p75NTR signalling was done by immunohistochemistry and immunoblotting. To assess the interaction between AraC and p75NTR, we performed cellular thermal shift and AraTM assays as well as Homo-FRET anisotropy imaging. We show that AraC induces neurite degeneration and programmed cell death of mature cerebellar granule neurons in a p75NTR-dependent manner. Mechanistically, Proline 252 and Cysteine 256 residues facilitate AraC interaction with the transmembrane domain of p75NTR resulting in uncoupling of p75NTR from the NFκB survival pathway. This, in turn, exacerbates the activation of the cell death/JNK pathway by recruitment of TRAF6 to p75NTR. Our findings identify p75NTR as a novel molecular target to develop treatments for counteract AraC-mediated cell death of mature neurons.",

author = "Vanessa Lopes-Rodrigues and Pia Boxy and Eunice Sim and Park, {Dong Ik} and Michael Habeck and Josep Carbonell and Annika Andersson and Diana Fern{\'a}ndez-Su{\'a}rez and Poul Nissen and Anders Nykj{\ae}r and Lilian Kisiswa",

year = "2023",

month = jul,

doi = "10.1038/s41419-023-05979-7",

language = "English",

volume = "14",

journal = "Cell Death and Disease",

issn = "2041-4889",

publisher = "Springer Nature",

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TY - JOUR

T1 - AraC interacts with p75NTR transmembrane domain to induce cell death of mature neurons

AU - Lopes-Rodrigues, Vanessa

AU - Boxy, Pia

AU - Sim, Eunice

AU - Park, Dong Ik

AU - Habeck, Michael

AU - Carbonell, Josep

AU - Andersson, Annika

AU - Fernández-Suárez, Diana

AU - Nissen, Poul

AU - Nykjær, Anders

AU - Kisiswa, Lilian

PY - 2023/7

Y1 - 2023/7

N2 - Cytosine arabinoside (AraC) is one of the main therapeutic treatments for several types of cancer, including acute myeloid leukaemia. However, after a high-dose AraC chemotherapy regime, patients develop severe neurotoxicity and cell death in the central nervous system leading to cerebellar ataxia, dysarthria, nystagmus, somnolence and drowsiness. AraC induces apoptosis in dividing cells. However, the mechanism by which it leads to neurite degeneration and cell death in mature neurons remains unclear. We hypothesise that the upregulation of the death receptor p75NTR is responsible for AraC-mediated neurodegeneration and cell death in leukaemia patients undergoing AraC treatment. To determine the role of AraC-p75NTR signalling in the cell death of mature neurons, we used mature cerebellar granule neurons’ primary cultures from p75NTR knockout and p75 NTRCys259 mice. Evaluation of neurite degeneration, cell death and p75NTR signalling was done by immunohistochemistry and immunoblotting. To assess the interaction between AraC and p75NTR, we performed cellular thermal shift and AraTM assays as well as Homo-FRET anisotropy imaging. We show that AraC induces neurite degeneration and programmed cell death of mature cerebellar granule neurons in a p75NTR-dependent manner. Mechanistically, Proline 252 and Cysteine 256 residues facilitate AraC interaction with the transmembrane domain of p75NTR resulting in uncoupling of p75NTR from the NFκB survival pathway. This, in turn, exacerbates the activation of the cell death/JNK pathway by recruitment of TRAF6 to p75NTR. Our findings identify p75NTR as a novel molecular target to develop treatments for counteract AraC-mediated cell death of mature neurons.

AB - Cytosine arabinoside (AraC) is one of the main therapeutic treatments for several types of cancer, including acute myeloid leukaemia. However, after a high-dose AraC chemotherapy regime, patients develop severe neurotoxicity and cell death in the central nervous system leading to cerebellar ataxia, dysarthria, nystagmus, somnolence and drowsiness. AraC induces apoptosis in dividing cells. However, the mechanism by which it leads to neurite degeneration and cell death in mature neurons remains unclear. We hypothesise that the upregulation of the death receptor p75NTR is responsible for AraC-mediated neurodegeneration and cell death in leukaemia patients undergoing AraC treatment. To determine the role of AraC-p75NTR signalling in the cell death of mature neurons, we used mature cerebellar granule neurons’ primary cultures from p75NTR knockout and p75 NTRCys259 mice. Evaluation of neurite degeneration, cell death and p75NTR signalling was done by immunohistochemistry and immunoblotting. To assess the interaction between AraC and p75NTR, we performed cellular thermal shift and AraTM assays as well as Homo-FRET anisotropy imaging. We show that AraC induces neurite degeneration and programmed cell death of mature cerebellar granule neurons in a p75NTR-dependent manner. Mechanistically, Proline 252 and Cysteine 256 residues facilitate AraC interaction with the transmembrane domain of p75NTR resulting in uncoupling of p75NTR from the NFκB survival pathway. This, in turn, exacerbates the activation of the cell death/JNK pathway by recruitment of TRAF6 to p75NTR. Our findings identify p75NTR as a novel molecular target to develop treatments for counteract AraC-mediated cell death of mature neurons.

UR - http://www.scopus.com/inward/record.url?scp=85165087088&partnerID=8YFLogxK

U2 - 10.1038/s41419-023-05979-7

DO - 10.1038/s41419-023-05979-7

M3 - Journal article

C2 - 37460457

AN - SCOPUS:85165087088

SN - 2041-4889

VL - 14

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 7

M1 - 440

ER -

AraC interacts with p75^NTR transmembrane domain to induce cell death of mature neurons

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