Biology subjects

Zamani, A.

Publications and source records attributed to Zamani, A..

3 recordsLinked to original sources

bioRxiv2026

CircZBTB46, a promising therapeutic target in crizotinib resistant ALK-positive T lymphomas

Circular RNAs (circRNAs) are increasingly recognized as functional non-coding transcripts with oncogenic potential. Here, a comprehensive analysis of circRNA expression in primary ALK(+) anaplastic large-cell lymphoma (ALK(+) ALCL) is presented. Integrated transcriptomic profiling revealed that aberrant expression of circZBTB46 and of its linear host transcript, normally restricted to dendritic cells, is exclusive to ALK(+) lymphoma cells and driven by the oncogenic NPM1-ALK/STAT3 axis. Functional studies showed that circZBTB46, unlike its protein-coding counterpart, promotes resistance to the ALK inhibitor crizotinib. Silencing circZBTB46 restored crizotinib sensitivity in resistant ALCL cells both in vitro and in vivo. Transcriptomic analyses identified PIP5K1C as a downstream effector regulated through a competitive endogenous RNA mechanism in which circZBTB46 acts as a sponge to miR-25-3p, alleviating its repression of PIP5K1C. These findings uncover a previously unrecognized mechanism of drug resistance in ALK(+) ALCL and establish circZBTB46 as a promising therapeutic target.

cancer biology↗

bioRxiv2022

Anti-NMDAR encephalitis antibodies cause long-lasting degradation of the hippocampal neural representation of memory

N-methyl D-aspartate receptor (NMDAR) encephalitis is an immune-mediated disorder characterized by a complex neuropsychiatric syndrome together with a reduction of NMDAR. Although in most patients the life-threatening symptoms of the acute stage resolve with immunotherapy, memory and executive functions remain altered for several months or years. A mechanistic explanation for these long-lasting cognitive effects is still lacking and previous animal models have not explored this effect. Here, we combined repeat calcium imaging of the same population of hundreds of hippocampal CA1 neurons for three months along with two behavioral tasks to assess retrograde and anterograde memory loss using a reported mouse model of cerebroventricular transfer of patients CSF antibodies. We measured how memory-related neuronal activity is affected by the presence of NMDAR antibodies during the induction of the model and its long-lasting recovery. In addition, we developed a computational model that provides a mechanistic explanation for the long-term antibody-mediated impairment of memory. The findings show that the presence of antibodies leads to an increase of CA1 neuronal firing rate, resulting in a reduction of the amount of information encoded by these cells. Furthermore, the antibodies cause a degradation of the hippocampal neuronal response stability over time, providing a neural correlate of memory dysfunction. All these neuronal alterations span the 3 months of recordings, and in some cases beyond the last recording point. The computational model shows that a reduction of NMDAR is sufficient to cause the changes observed in neuronal activity, including the different involvement of excitatory and inhibitory inputs to CA1 neurons. Altogether, we show that the antibody-mediated reduction of NMDAR leads to long-term changes in hippocampal neuronal activity which extend far beyond the antibody clearance, providing a mechanism that can account for the cognitive deficits observed in the protracted recovery of patients with anti-NMDAR encephalitis.

neuroscience↗

bioRxiv2020

Acute treatment with TrkB agonist LM22A-4 confers neuroprotection and preserves myelin integrity in a mouse model of pediatric traumatic brain injury

Young children have a high risk of sustaining a traumatic brain injury (TBI), which can have debilitating life-long consequences. Importantly, the young brain shows particular vulnerability to injury, likely attributed to ongoing maturation of the myelinating nervous system at the time of insult. Here, we examined the effect of acute treatment with partial tropomyosin receptor kinase B (TrkB) agonist, LM22A-4, on the pathological and neurobehavioral outcomes after pediatric TBI, with the hypothesis that targeting TrkB would minimize tissue damage and support functional recovery. We focused on myelinated tracts-- the corpus callosum and external capsules--based on recent evidence that TrkB activation potentiates oligodendrocyte remyelination. Male mice at postnatal day 21 received an experimental TBI or sham surgery. Acutely post-injury, extensive cell death, a robust glial response and disruption of compact myelin were evident in the injured brain. TBI or sham mice then received intranasal saline vehicle or LM22A-4 for 14 days. Behavior testing was performed from 4 weeks post-injury, and brains were collected at 5 weeks for histology. TBI mice showed hyperactivity, reduced anxiety-like behavior, and social memory impairments. LM22A-4 ameliorated the abnormal anxiolytic phenotype but had no effect on social memory deficits. Use of spectral confocal reflectance microscopy detected persistent myelin fragmentation in the external capsule of TBI mice at 5 weeks post-injury, which was accompanied by regionally distinct deficits in oligodendrocyte progenitor cells and postmitotic oligodendrocytes, as well as chronic reactive gliosis and atrophy of the corpus callosum and injured external capsule. LM22A-4 treatment ameliorated myelin deficits in the perilesional external capsule, as well as tissue volume loss and the extent of reactive gliosis. However, there was no effect of this TrkB agonist on oligodendroglial populations detected at 5 weeks post-injury. Collectively, our results demonstrate that targeting TrkB immediately after TBI during early life confers neuroprotection and preserves myelin integrity, and this was associated with some improved neurobehavioral outcomes as the pediatric injured brain matures.

neuroscience↗