Commentary
Abstract
N-methyl-d-aspartate (NMDA) receptor–mediated autoimmune encephalitis (NMDAR-AE) is the most common cause of autoimmune encephalitis, especially in children and young adults. The disorder is caused by antibodies directed against the GluN1 protein, an obligatory constituent of NMDA receptors, which are key signaling molecules in brain development, learning and memory, and executive function. The manuscript by Zhou et al. offers key insights into aberrant development of cortical pathways that may underly persistent sensorimotor deficits associated with this encephalitis in a newly generated mouse model. This study convincingly links transient exposure to a patient-derived anti-GluN1 mAb during a critical developmental period to lasting disruptions in interhemispheric connectivity through callosal projections. These findings provide insight into the impact of a prevalent autoimmune disorder on fundamental aspects of brain development and establish a model system that could be further employed to probe other aspects of NMDAR-AE pathogenesis.
Authors
Puneet Opal, Geoffrey T. Swanson
Abstract
Cellular senescence is a cell state induced by irreparable cellular damage. The hallmark of senescence is cell cycle exit, yet neurons, which are postmitotic from birth, have also been found to undergo senescence. Neuronal senescence is prevalent in aging as well as in neurodegenerative disease. However, a role for senescence in epilepsy is virtually unexplored. In this issue of the JCI, Ge and authors used resected brain tissue from individuals with drug-resistant epilepsy, a genetic knockout mouse model, and a chemoconvulsant mouse model, to demonstrate a subset of cortical pyramidal senescent neurons that likely contribute to the pathophysiology of epilepsy. These findings highlight senescence as a possible target in precision-therapy approaches for epilepsy and warrant further investigation.
Authors
Gemma L Carvill
Abstract
Ischemic stroke causes scars in the CNS that impede functional recovery, and there is a need for therapeutics to improve recovery after the acute phase. Scar-resident myofibroblasts and the PDGF pathway have been implicated in stroke pathology. In this issue of the JCI, Protzmann et al. report that inhibition of PDGF-CC or its receptor, PDGFRα, reduces the myofibroblast population and improves functional recovery after ischemic stroke in mice. Importantly, PDGFRα inhibition was effective in improving functional recovery even when initiated 24 hours after stroke, which suggests opportunities for later treatment by targeting the PDGF pathway. This study demonstrates the therapeutic potential of enhancing stroke recovery even after acute damage and blood-brain barrier dysfunction has already occurred.
Authors
Hae Ryong Kwon, Lorin E. Olson
Abstract
Nerve growth factor (NGF) signaling is a clinically validated target for the treatment of several prevalent types of chronic pain; however, addressing safety concerns remain a key challenge. In this issue of the JCI, Peach et al. take a major step forward in this area by deciphering complexities in the signaling of the NGF receptor TrkA, finding that neuropilin 1 (NRP1) acted as a coreceptor for NGF actions at TrkA and the receptor complex required scaffolding from GIPC1. Using a mix of techniques, including animal behavioral models, electrophysiology on mouse and human dorsal root ganglion (DRG) neurons, and elegant biochemical pharmacology, the authors demonstrated that this therapeutic target might more safely manipulate NGF signaling to achieve pain alleviation. While there are still important questions to answer, the innovative work paves the way for the development of nonopioid pain therapeutics.
Authors
Andi Wangzhou, Theodore J. Price
Abstract
Chronic pain is a debilitating condition that affects up to 1.5 billion people globally. Advancing pain management depends on a thorough understanding of the types of pain experienced by patients and the underlying mechanisms driving it. N-type calcium channels play a crucial role as therapeutic targets for managing chronic pain. In this issue of the JCI, Tang et al. introduce C2230, an N-type calcium channel blocker that inhibited CaV2.2 channels during high frequency stimulation with little effect on other ion channels in the pain pathway across multiple models. C2230 offers a promising analgesic for use in therapeutic intervention.
Authors
Maria A. Gandini, Gerald W. Zamponi
Abstract
Truncation variants in the gene TTN encoding titin are the most common cause of familial dilated cardiomyopathy (DCM), with both haploinsufficiency and “poison peptide” implicated as contributory mechanisms of disease. In this issue of the JCI, Kim et al. identify a highly conserved enhancer element approximately 500 bp downstream of the transcriptional start site of TTN in intron 1, which they demonstrated to be critical in regulating TTN expression. This work helps to further clarify the relative role of haploinsufficiency in TTN-related DCM and provides a potential target for therapies aimed at treating TTN-related DCM.
Authors
Dominic E. Fullenkamp
Abstract
Lysosome storage dysfunction plays a central role in numerous human diseases, but a lack of appropriate tools has hindered lysosomal content profiling in clinical settings. In this issue of the JCI, Saarela et al. introduce a method called tagless LysoIP that enabled rapid isolation of intact lysosomes from blood and brain cells via immunoprecipitation of the endogenous protein TMEM192. Applied to the neurodegenerative lysosomal storage disorder known as Batten disease (caused by mutations in the CLN3 gene), tagless LysoIP revealed substantial accumulation of glycerophosphodiesters (GPDs) in patient lysosomes. These findings highlight the role of CLN3 in GPD clearance and present an innovative method that will enable biomarker discovery and therapeutic advancement in lysosomal diseases.
Authors
Ali Shilatifard, Issam Ben-Sahra
Abstract
Serologic biomarkers for the early diagnosis of EBV-associated nasopharyngeal carcinoma (NPC) have been identified from population studies, but a protective antibody signature in cancer-free seropositive carriers remains undefined. In this issue of the JCI, Kong et al. show that high levels of IgG against EBV glycoprotein 42 (gp42) were associated with reduced NPC risk in three independent prospective cohorts from southern China. EBV virions contain gp42, which complexes with gH-gL to facilitate fusion with B cells by binding to HLA class II (HLA-II). In this study, HLA-II was detected on non-antigen-presenting cells in a proportion of premalignant nasopharyngeal tissues, which may prime the nasopharyngeal epithelium for infection. In vitro, HLA-II expression in a nasopharyngeal cell line encouraged infection by EBV derived from B cells or epithelial cells. These findings suggest that a vaccine that stimulates gp42-IgG production may reduce the risk of EBV-associated NPC in endemic regions.
Authors
Benjamin E. Warner, Kathy H.Y. Shair
Abstract
The precise mechanisms of blood pressure (BP) regulation are not fully elucidated, and understanding BP regulation is crucial for managing hypertension and improving outcomes for cardiovascular disease. In this issue of the JCI, Wang et al. identified the transcription factor PR domain–containing protein 16 (PRDM16) as a regulator of both vascular smooth muscle cell contraction and the circadian response to BP control. PRDM16 directly transcriptionally controlled the expression of the adrenergic receptor α 1d and several clock genes crucial for BP circadian regulation. These findings identify a mechanism of how molecular pathways govern circadian BP variation, highlighting PRDM16 as a potential target for hypertension.
Authors
M. Adriana Cuibus, Omar Abdel-Wahab
Abstract
Colorectal cancer is the second leading cause of cancer death in the United States. The adenomatous polyposis coli (APC) pathway plays a critical role in colorectal tumorigenesis, but the mechanism is not fully understood. In this issue of the JCI, Luo and colleagues used genetically engineered mouse models to show that high mobility group A (HMGA1) is a critical mediator in the development of colon tumors driven by the loss of the Apc gene. HMGA1 activated the transcription of Achaete-Scute Family BHLH Transcription Factor 2 (ASCL2), which regulated intestinal stemness and promoted colon tumorigenesis.
Authors
Yuxiang Wang, Mikayla Ybarra, Zhenghe Wang
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