RESUMEN
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 p75NTRCys259 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.
Asunto(s)
Neuronas , Receptores de Factor de Crecimiento Nervioso , Animales , Ratones , Apoptosis/fisiología , Muerte Celular , Células Cultivadas , Neuritas/metabolismo , Neuronas/metabolismo , Receptor de Factor de Crecimiento Nervioso/metabolismo , Receptores de Factor de Crecimiento Nervioso/genética , Receptores de Factor de Crecimiento Nervioso/metabolismoRESUMEN
The cerebellum is a multifunctional brain region that controls diverse motor and non-motor behaviors. As a result, impairments in the cerebellar architecture and circuitry lead to a vast array of neuropsychiatric and neurodevelopmental disorders. Neurotrophins and neurotrophic growth factors play essential roles in the development as well as maintenance of the central and peripheral nervous system which is crucial for normal brain function. Their timely expression throughout embryonic and postnatal stages is important for promoting growth and survival of both neurons and glial cells. During postnatal development, the cerebellum undergoes changes in its cellular organization, which is regulated by a variety of molecular factors, including neurotrophic factors. Studies have shown that these factors and their receptors promote proper formation of the cerebellar cytoarchitecture as well as maintenance of the cerebellar circuits. In this review, we will summarize what is known on the neurotrophic factors' role in cerebellar postnatal development and how their dysregulation assists in developing various neurological disorders. Understanding the expression patterns and signaling mechanisms of these factors and their receptors is crucial for elucidating their function within the cerebellum and for developing therapeutic strategies for cerebellar-related disorders.