Gene therapy for Dravet syndrome: promises and impact on disease trigger and secondary modifications DOI Open Access
Claudia Di Berardino, Luca Massimino, Federica Ungaro

et al.

Rare Disease and Orphan Drugs Journal, Journal Year: 2024, Volume and Issue: 3(3)

Published: July 9, 2024

Dravet syndrome is a severe epileptic that begins during the first year of life otherwise healthy babies. Over years, seizure burden changes, and pathology evolves in strong association with behavioral alterations, including cognitive delay autistic traits. Initially, this aspect was considered direct consequence epilepsy severity, DS defined as an encephalopathy. Increasing evidence suggests these two aspects disease, impairment, might not be so strictly connected. mostly caused by heterozygous loss-of-function mutations SCN1A gene, which encodes for alpha-subunit voltage-gated sodium channel Nav1.1, responsible GABAergic interneuron excitability. Interneuron dysfunction evident at symptom onset murine models, but their activity appears to recover chronic phase when series secondary modifications arise likely drive phenotype. Given genetic basis disease clear, innovative therapies based on restoration sufficient expression levels Nav1.1 re-establish functional neuronal are being developed. In work, we review such therapeutic approaches, specific focus existing ability address only also modifications.

Language: Английский

Transcriptomic analyses of human brains with Alzheimer disease identified dysregulated epilepsy-causing genes DOI Creative Commons
Abdallah M. Eteleeb,

Suélen Santos Alves,

Stephanie S. Buss

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Abstract Background & Objective Alzheimer’s Disease (AD) patients at multiple stages of disease progression have a high prevalence seizures. However, whether AD and epilepsy share pathophysiological changes remains poorly defined. In this study, we leveraged high-throughput transcriptomic data from sporadic cases different cognitive impairment across independent cohorts brain regions to examine the role epilepsy-causing genes. Methods Epilepsy-causing genes were manually curated, their expression levels analyzed bulk three regions. RNA-seq control Knight ADRC, MSBB, ROSMAP processed under same analytical pipeline. An integrative clustering approach employing machine learning multi-omics was employed identify molecularly defined profiles with scores. Results We found several epilepsy-associated genes/pathways significantly dysregulated in group more severe impairment. observed 15 consistently downregulated cohorts, including sodium potassium channels, suggesting that these play fundamental roles function or progression. Notably, 25 earlier become worse Conclusion Our findings showed early late progression, they might be playing can not establish directionality cause-effect our findings. underlie presence seizures patients, which present before concurrently initial AD.

Language: Английский

Citations

0
Astrocytic pleiotrophin deficiency in the prefrontal cortex contributes to stress-induced depressive-like responses in male mice DOI Creative Commons
Dongmei Chi, Kun Zhang, Jianxing Zhang

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 14, 2025

Astrocytes are closely linked to depression, and the prefrontal cortex (PFC) is an important brain region involved in major depressive disorder (MDD). However, underlying mechanism by which astrocytes within PFC contribute MDD remains unclear. Using single-nucleus RNA sequencing analyses, we show a significant reduction attenuated pleiotrophin-protein tyrosine phosphatase receptor type Z1 (PTN-PTPRZ1) signaling astrocyte-to-excitatory neuron communication of male patients. We find reduced PTN dorsomedial mice with depression induced chronic restraint social defeat stress. Knockdown astrocytic induces depression-related responses, reversed exogenous supplementation or overexpression PTN. The antidepressant effects exerted require interaction PTPRZ1 excitatory neurons, PTN-PTPRZ1 activates AKT pathway regulate responses. Our findings indicate PTN-PTPRZ1-AKT may be potential therapeutic target for MDD. but mechanisms remain Here, authors that pleiotrophin contributes depression-like phenotype mice.

Language: Английский

Citations

0
Brain connectivity and transcriptional changes induced by rTMS in first-episode major depressive disorder DOI Creative Commons
Muzhen Guan, Yuanjun Xie,

Zhongheng Wang

et al.

Translational Psychiatry, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 24, 2025

Repetitive transcranial magnetic stimulation (rTMS) is a widely utilized non-invasive brain technique with demonstrated efficacy in treating major depressive disorder (MDD). However, the mechanisms underlying its therapeutic effects, particularly modulating neural connectivity and influencing gene expression, remain incompletely understood. In this study, we investigated voxel-wise degree centrality (DC) induced by 10 Hz rTMS targeting left dorsolateral prefrontal cortex, as well their associations transcriptomic data from Allen Human Brain Atlas. The results indicated that active treatment significantly reduced clinical symptoms increased DC superior medial frontal gyrus, middle occipital right anterior cingulate cortex. Partial least squares regression analysis revealed genes associated alternations were enriched biological processes related to plasticity synaptic connectivity. Furthermore, protein-protein interaction (PPI) identified key hub genes, including SCN1A, SNAP25, PVALB, whose expression levels positively correlated changes. Notably, SCN1A emerged significant predictor on These findings suggest may exert effects MDD specific molecular pathways networks, providing valuable insights into of action.

Language: Английский

Citations

0
Psychological and physiological computing based on multi-dimensional foot information DOI Creative Commons
Shengyang Li,

Huilin Yao,

Ruotian Peng

et al.

Artificial Intelligence Review, Journal Year: 2025, Volume and Issue: 58(5)

Published: Feb. 15, 2025

Language: Английский

Citations

0
Altered synaptic homeostasis: a key factor in the pathophysiology of depression DOI Creative Commons
Bin Wang,

Teng He,

Guihong Qiu

et al.

Cell & Bioscience, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 25, 2025

Abstract Depression, a widespread psychiatric disorder, is characterized by diverse array of symptoms such as melancholic mood and anhedonia, imposing significant burden on both society individuals. Despite extensive research into the neurobiological foundations depression, complete understanding its complex mechanisms yet to be attained, targeted therapeutic interventions remain under development. Synaptic homeostasis, compensatory feedback mechanism, involves neurons adjusting synaptic strength regulating pre- or postsynaptic processes. Recent advancements in depression reveal crucial association between disorder disruptions homeostasis within neural regions circuits pivotal for emotional cognitive functions. This paper explores governing focusing role ion channels, regulation presynaptic neurotransmitter release, scaling processes, essential signaling molecules. By mapping new pathways study it pertains this aims provide valuable insights identifying novel targets more effective antidepressant treatments.

Language: Английский

Citations

0
Transcriptomic analyses of human brains with Alzheimer’s disease identified dysregulated epilepsy-causing genes DOI
Abdallah M. Eteleeb,

Suélen Santos Alves,

Stephanie S. Buss

et al.

Epilepsy & Behavior, Journal Year: 2025, Volume and Issue: 168, P. 110421 - 110421

Published: April 17, 2025

Language: Английский

Citations

0
Gene therapy for Dravet syndrome: promises and impact on disease trigger and secondary modifications DOI Open Access
Claudia Di Berardino, Luca Massimino, Federica Ungaro

et al.

Rare Disease and Orphan Drugs Journal, Journal Year: 2024, Volume and Issue: 3(3)

Published: July 9, 2024

Dravet syndrome is a severe epileptic that begins during the first year of life otherwise healthy babies. Over years, seizure burden changes, and pathology evolves in strong association with behavioral alterations, including cognitive delay autistic traits. Initially, this aspect was considered direct consequence epilepsy severity, DS defined as an encephalopathy. Increasing evidence suggests these two aspects disease, impairment, might not be so strictly connected. mostly caused by heterozygous loss-of-function mutations SCN1A gene, which encodes for alpha-subunit voltage-gated sodium channel Nav1.1, responsible GABAergic interneuron excitability. Interneuron dysfunction evident at symptom onset murine models, but their activity appears to recover chronic phase when series secondary modifications arise likely drive phenotype. Given genetic basis disease clear, innovative therapies based on restoration sufficient expression levels Nav1.1 re-establish functional neuronal are being developed. In work, we review such therapeutic approaches, specific focus existing ability address only also modifications.

Language: Английский

Citations

0