Ganguly et al. report that 3βHSD1 promotes therapeutic resistance in prostate cancer by upregulating intratumoral androgen biosynthesis and DNA double-strand break repair. The cover image depicts the testosterone biosynthesis pathway surrounding a radiotherapy-resistant prostate tumor. Image credit: Dave Schumick.
Current treatments for neurodegenerative diseases and neural injuries face major challenges, primarily due to the diminished regenerative capacity of neurons in the mammalian central nervous system (CNS) as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulating mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons following peripheral nerve injury to facilitate spontaneous axon regeneration. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via both histone methylation-dependent and -independent mechanisms. Further investigation revealed that Ezh2 fostered axon regeneration by orchestrating the transcriptional silencing of genes governing synaptic function and those inhibiting axon regeneration, while concurrently activating various factors that support axon regeneration. Notably, we demonstrated that GABA transporter 2 encoded by Slc6a13 acted downstream of Ezh2 to control axon regeneration. Overall, our study underscores the potential of modulating chromatin accessibility as a promising strategy for promoting CNS axon regeneration.
Xue-Wei Wang, Shu-Guang Yang, Ming-Wen Hu, Rui-Ying Wang, Chi Zhang, Anish R. Kosanam, Arinze J. Ochuba, Jing-Jing Jiang, Ximei Luo, Yun Guan, Jiang Qian, Chang-Mei Liu, Feng-Quan Zhou
Blood–brain barrier (BBB) disruption is a serious pathological consequence of traumatic brain injury (TBI), for which there are limited therapeutic strategies. Tissue inhibitor of metalloproteinase-2 (TIMP2), a molecule with dual functions of inhibiting matrix metalloproteinase (MMP) activity and displaying cytokine-like activity through receptor binding, has been reported to inhibit VEGF-induced vascular hyperpermeability. Here, we investigate the ability of TIMP2 to ameliorate BBB disruption in TBI and the underlying molecular mechanisms. Both TIMP2 and AlaTIMP2, a TIMP2 mutant without MMP-inhibiting activity, attenuated neurological deficits and BBB leakage in TBI mice, as well as inhibited junctional protein degradation and translocation to reduce paracellular permeability in HBMECs exposed to hypoxic plus inflammatory insult. Mechanistic studies revealed that TIMP2 interacted with integrin α3β1 on endothelial cells (ECs), inhibiting Src activation-dependent VE-Cadherin phosphorylation, VE-Cadherin/catenin complex destabilization and subsequent VE-Cadherin internalization. Notably, localization of VE-Cadherin on the membrane was critical for TIMP2-mediated EC barrier integrity. Furthermore, TIMP2-mediated increased membrane localization of VE-Cadherin enhanced the level of active Rac1, thereby inhibiting stress fiber formation. Together, our studies have identified an MMP-independent mechanism by which TIMP2 regulates EC barrier integrity after TBI. TIMP2 may be a therapeutic agent for TBI and other neurological disorders involving BBB breakdown.
Jingshu Tang, Yuying Kang, Yujun Zhou, Nianying Shang, Xinnan Li, Hongyue Wang, Jiaqi Lan, Shuai Wang, Lei Wu, Ying Peng
Vascular aging impacts multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular read-outs, remain vastly incomplete. Here we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and uncovered that Notch3 inactivation alters regulation of calcium, contractile function, and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of CADASIL patients – a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3 null mice has unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.
Milagros C. Romay, Russell H. Knutsen, Feiyang Ma, Ana Mompeón, Gloria E. Hernandez, Jocelynda Salvador, Snezana Mirkov, Ayush Batra, David P. Sullivan, Daniele Procissi, Samuel Buchanan, Elise Kronquist, Elisa A. Ferrante, William A. Muller, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Craig Horbinski, Elisabeth Tournier‑Lasserve, Adam M. Sonabend, Farzaneh A. Sorond, MichaelM. Wang, Manfred Boehm, Beth A. Kozel, M. Luisa Iruela-Arispe
C1q/TNF related protein 4 (CTRP4) is generally thought to be released extracellularly and plays a critical role in energy metabolism and protecting against sepsis. However, its physiological functions in autoimmune diseases have not been thoroughly explored. In this study, we demonstrated that Th17 cell-associated experimental autoimmune encephalomyelitis was greatly exacerbated in Ctrp4-/- mice compared to WT mice due to increased Th17 cell infiltration. The absence of Ctrp4 promoted the differentiation of naïve CD4+ T cells into Th17 cells in vitro. Mechanistically, CTRP4 interferes with the interaction between IL-6 and IL-6R by directly competing to bind with IL-6R leading to suppression of IL-6-induced activation of STAT3 pathway. Furthermore, the administration of recombinant CTRP4 protein ameliorated the disease symptoms. In conclusion, our results indicate that CTRP4, as an endogenous regulator of the IL-6 receptor signaling pathway, may be a potential therapeutic intervention for Th17 driven-autoimmune diseases.
Lulu Cao, Jinhai Deng, Wei Chen, Minwei He, Ning Zhao, He Huang, Lu Ling, Qi Li, Xiaoxin Zhu, Lu Wang
Glycogen storage disease type III (GSDIII) is a rare inborn error of metabolism affecting liver, skeletal muscle, and heart due to mutations of the AGL gene encoding for the glycogen debranching enzyme (GDE). No curative treatment exists for GSDIII. The 4.6 kb GDE cDNA represents the major technical challenge toward the development of a single recombinant adeno-associated virus (rAAV)-derived vector gene therapy strategy. Using information on GDE structure and molecular modeling, we generated multiple truncated GDEs retaining activity. Among them, an N-terminal-truncated mutant ∆Nter2-GDE had a similar efficacy in vivo compared to the full-size enzyme. A rAAV vector expressing ∆Nter2-GDE allowed significant glycogen reduction in heart and muscle of Agl–/– mice three months after intravenous injection, as well as normalization of histology features and restoration of muscle strength. Similarly, glycogen accumulation and histological features were corrected in a recently generated Agl–/– rat model. Finally, transduction with rAAV vectors encoding ∆Nter2-GDE corrected glycogen accumulation in an in vitro human skeletal muscle cellular model of GSDIII. In conclusion, our results demonstrated the ability of a single rAAV vector expressing a functional mini-GDE transgene to correct the muscle and heart phenotype in multiple models of GSDIII, supporting its clinical translation to GSDIII patients.
Antoine Gardin, Jérémy Rouillon, Valle Montalvo-Romeral, Lucille Rossiaud, Patrice Vidal, Romain Launay, Mallaury Vie, Youssef Krimi Benchekroun, Jérémie Cosette, Bérangère Bertin, Tiziana La Bella, Guillaume Dubreuil, Justine Nozi, Louisa Jauze, Romain Fragnoud, Nathalie F. Daniele, Laetitia Van Wittenberghe, Jérémy Esque, Isabelle André, Xavier Nissan, Lucile Hoch, Giuseppe Ronzitti
JCI This Month is a digest of the research, reviews, and other features published each month.
The lungs are regularly exposed to airborne irritants, pathogens, and other sources of inflammation that cause injury to the lung epithelium and its underlying structure. Repair and regeneration are essential for healthy lung function throughout life, yet these processes can also influence development and progression of acute and chronic conditions. Series editor Suzanne Herold developed this review series on lung inflammatory injury and tissue repair to reveal the many cell populations involved in normal and aberrant reparative responses. Ranging from discussion of lung stroma and vasculature to adaptive and innate immune systems, the reviews in this series describe the many complex mechanisms that influence pathogen-, inflammation-, and aging-driven injury to the lung and can contribute to aberrant healing, resolution of inflammation, and fibrosis. Reviews also discuss a wide range of potential therapies targeting injury and repair processes that represent promising progress toward better clinical options for patients with acute and chronic lung conditions.