Neuroscience
Abstract
Neurofilament accumulation is associated with many neurodegenerative diseases, but it is the primary pathology in giant axonal neuropathy (GAN). This childhood-onset autosomal recessive disease is caused by loss-of-function mutations in gigaxonin, the E3 adaptor protein that enables neurofilament degradation. Using a combination of genetic and RNA interference approaches, we found that dorsal root ganglia from mice lacking gigaxonin have impaired autophagy and lysosomal degradation through 2 mechanisms. First, neurofilament accumulations interfere with the distribution of autophagic organelles, impairing their maturation and fusion with lysosomes. Second, the accumulations attract the chaperone 14-3-3, which is responsible for the proper localization of the key autophagy regulator transcription factor EB (TFEB). We propose that this dual disruption of autophagy contributes to the pathogenesis of other neurodegenerative diseases involving neurofilament accumulations.
Authors
Jean-Michel Paumier, James Zewe, Chiranjit Panja, Melissa R. Pergande, Meghana Venkatesan, Eitan Israeli, Shikha Prasad, Natasha Snider, Jeffrey N. Savas, Puneet Opal
Abstract
Systemic lupus erythematosus (SLE), an autoimmune disease, can cause psychiatric disorders, particularly depression, via immune activation. Human umbilical cord mesenchymal stromal cell (hUCMSC) transplantation (MSCT) has been shown to ameliorate immune dysfunction in SLE by inducing immune tolerance. However, whether MSCT can relieve the depressive symptoms in SLE remains incompletely understood. Here, we demonstrate that MSCT relieved early-onset depression-like behavior in both genetic lupus-prone (MRL/lpr) and pristane-induced lupus mice by rescuing impaired hippocampal synaptic connectivity. Transplanted hUCMSCs targeted Th1 cell-derived IFNγ to inhibit neuronal JAK-STAT1 signaling and downstream CCL8 expression, reducing phagocytic microglia apposition to alleviate synaptic engulfment and neurological dysfunction in young (8-week-old) lupus mice. Systemic delivery of exogenous IFNγ blunted MSCT-mediated alleviation of synaptic loss and depressive behavior in lupus mice, suggesting that the IFNγ-CCL8 axis may be an effective therapeutic target and that MSCT is a potential therapy for lupus-related depression. In summary, transplanted hUCMSCs can target systemic immunity to ameliorate psychiatric disorders by rescuing synaptic loss, highlighting the active role of neurons as intermediaries between systemic immunity and microglia in this process.
Authors
Han Xiaojuan, Dandan Wang, Liang Chen, Hua Song, Xiulan Zheng, Xin Zhang, Shengnan Zhao, Jun Liang, Tianshu Xu, Zhibin Hu, Lingyun Sun
Abstract
Prader-Willi syndrome (PWS) is a multigenic disorder caused by the loss of seven contiguous paternally expressed genes. Mouse models with inactivation of all PWS genes are lethal. Knockout (KO) mouse models for each candidate gene have been generated, but they lack the functional interactions between PWS genes. Here, we revealed an interplay between Necdin and Magel2 “PWS” genes and generated a mouse model (named “Del Ndn-Magel2” mice) with a deletion including both genes. A subset of Del Ndn-Magel2 mice showed neonatal lethality. Behaviorally, surviving mutant mice exhibited sensory delays during infancy and alterations in social exploration at adulthood. Del Ndn-Magel2 mice had a lower body weight before weaning, persisting after weaning in males only, with reduced fat mass and improved glucose tolerance, and altered puberty. Adult mutant mice displayed increased ventilation and a persistent increase in apneas following a hypercapnic challenge. Transcriptomics analyses revealed a dysregulation of key circadian genes and alterations of genes associated with axonal function similar to PWS patients. At neuroanatomical levels, Del Ndn-Magel2 mice had an impaired maturation of oxytocin neurons and a disrupted development of melanocortin circuits. Together, these data indicate that the Del Ndn-Magel2 mouse is a pertinent and genetically relevant model of PWS
Authors
Pierre-Yves Barelle, Alicia Sicardi, Fabienne Schaller, Julie Buron, Denis Becquet, Felix Omnes, Françoise Watrin, Marie-Sophie Alifrangis, Catarina Santos, Clément Menuet, Anne-Marie François-Bellan, Emilie Caron, Jessica Klucznik, Vincent Prevot, Sebastien G. Bouret, Françoise Muscatelli
Abstract
The use of genetically engineered tools, including combinations of Cre-LoxP and Flp-FRT systems, enable the interrogation of complex biology. Steroidogenic factor-1 (SF-1) is expressed in the ventromedial hypothalamic nucleus (VMH). Development of genetic tools, such as mice expressing Flp recombinase (Flp) in SF-1 neurons (Sf-1-Flp), will be useful for future studies that unravel the complex physiology regulated by the VMH. Here, we developed and characterized Sf-1-Flp mice and demonstrated its utility. Flp sequence was inserted into Sf-1 locus with P2A. This insertion did not affect Sf-1 mRNA expression levels and Sf-1-Flp mice do not have any visible phenotypes. They are fertile and metabolically comparable to wild-type littermate mice. Optogenetic stimulation using adeno-associated virus (AAV)-bearing Flp-dependent channelrhodopsin-2 (ChR2) increased blood glucose and skeletal muscle PGC-1α in Sf-1-Flp mice. This was similar to SF-1 neuronal activation using Sf-1-BAC-Cre and AAV-bearing Cre-dependent ChR2. Finally, we generated Sf-1-Flp mice that lack β2-adrenergic receptors (Adrβ2) only in skeletal muscle with a combination of Cre/LoxP technology (Sf-1-Flp::SKM∆Adrβ2). Optogenetic stimulation of SF-1 neurons failed to increase skeletal muscle PGC-1α in Sf-1-Flp::SKM∆Adrβ2 mice, suggesting that Adrβ2 in skeletal muscle is required for augmented skeletal muscle PGC-1α by SF-1 neuronal activation. Our data demonstrate that Sf-1-Flp mice are useful for interrogating complex physiology.
Authors
Marco Galvan, Mina Fujitani, Samuel R. Heaselgrave, Shreya Thomas, Bandy Chen, Jenny J. Lee, Steven C. Wyler, Joel K. Elmquist, Teppei Fujikawa
Abstract
Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid kidney failure induced by Mdm2 conditional deletion in the kidney tubules to interrogate kidney and brain metabolism. Pathway enrichment analysis of focused plasma metabolomics panel pinpointed tryptophan metabolism as the most altered pathway with kidney failure. Spatial metabolomics showed toxic tryptophan metabolites in the kidneys and brains, revealing a connection between advanced kidney disease and accelerated kynurenine degradation. In particular, the excitotoxic metabolite quinolinic acid was localized in ependymal cells in the setting of kidney failure. These findings were associated with brain inflammation and cell death. Separate mouse models of ischemia-induced acute kidney injury and adenine-induced chronic kidney disease also exhibited systemic inflammation and accumulating toxic tryptophan metabolites. Patients with advanced CKD (stage 3B-4, n = 18 and stage 5, n = 8), similarly demonstrated elevated plasma kynurenine metabolites and quinolinic acid was uniquely correlated with fatigue and reduced quality of life. Overall, our study identifies the kynurenine pathway as a bridge between kidney decline, systemic inflammation, and brain toxicity, offering potential avenues for diagnosis and treatment of neurological issues in kidney disease.
Authors
Afaf Saliba, Subrata Debnath, Ian Tamayo, Hak Joo Lee, Nagarjunachary Ragi, Falguni Das, Richard Montellano, Jana Tumova, Meyer Maddox, Esmeralda Trevino, Pragya Singh, Caitlyn Fastenau, Soumya Maity, Guanshi Zhang, Leila Hejazi, Manjeri A. Venkatachalam, Jason C. O'Connor, Bernard Fongang, Sarah C. Hopp, Kevin F. Bieniek, James D. Lechleiter, Kumar Sharma
Abstract
Dravet syndrome is a developmental and epileptic encephalopathy associated with pathogenic variants in SCN1A. Most disease-causing variants are located within coding regions, but recent work has shed light on the role of non-coding variants associated with a poison exon in intron 20 of SCN1A. Discovery of the SCN1A poison exon known as 20N has led to the first potential disease-modifying therapy for Dravet syndrome in the form of an antisense oligonucleotide. Here, we demonstrate the existence of two additional poison exons in introns 1 and 22 of SCN1A through targeted, deep-coverage long-read sequencing of SCN1A transcripts. We show that inclusion of these poison exons is developmentally regulated in the human brain, and that deep intronic variants associated with these poison exons lead to their aberrant inclusion in vitro in a minigene assay or in iPSC-derived neurons. Additionally, we show that splice-modulating antisense oligonucleotides (ASOs) can ameliorate aberrant inclusion of poison exons. Our findings highlight the role of deep intronic pathogenic variants in disease and provide additional therapeutic targets for precision medicine in Dravet syndrome and other SCN1A-related disorders.
Authors
Sheng Tang, Hannah Stamberger, Jeffrey D. Calhoun, Sarah Weckhuysen, Gemma L. Carvill
Abstract
Elevation of intraocular pressure (IOP) due to trabecular meshwork (TM) dysfunction, leading to neurodegeneration, is the pathological hallmark of primary open-angle glaucoma (POAG). Impaired axonal transport is an early and critical feature of glaucomatous neurodegeneration. However, a robust mouse model that accurately replicates these human POAG features has been lacking. We report the development and characterization of a novel Cre-inducible mouse model expressing a DsRed-tagged Y437H mutant of human myocilin (Tg.CreMYOCY437H). A single intravitreal injection of HAd5-Cre induced selective MYOC expression in the TM, causing TM dysfunction, reducing the outflow facility, and progressively elevating IOP in Tg.CreMYOCY437H mice. Sustained IOP elevation resulted in significant loss of retinal ganglion cells (RGCs) and progressive axonal degeneration in Cre-induced Tg.CreMYOCY437H mice. Notably, impaired anterograde axonal transport was observed at the optic nerve head before RGC degeneration, independent of age, indicating that impaired axonal transport contributes to RGC degeneration in Tg.CreMYOCY437H mice. In contrast, axonal transport remained intact in ocular hypertensive mice injected with microbeads, despite significant RGC loss. Our findings indicate that Cre-inducible Tg.CreMYOCY437H mice replicate all glaucoma phenotypes, providing an ideal model for studying early events of TM dysfunction and neuronal loss in POAG.
Authors
Balasankara Reddy Kaipa, Ramesh Kasetti, Yogapriya Sundaresan, Linya Li, Sam Yacoub, J. Cameron Millar, William Cho, Dorota Skowronska-Krawczyk, Prabhavathi Maddineni, Krzysztof Palczewski, Gulab S. Zode
Abstract
Cerebral endothelial cell (EC) injury and blood-brain barrier (BBB) permeability contribute to neuronal injury in acute neurological disease states. Preclinical experiments have used animal models to study this phenomenon, yet the response of human cerebral ECs to BBB disruption remains unclear. In our Phase 1 clinical trial (NCT04528680), we used low-intensity pulsed ultrasound with microbubbles (LIPU/MB) to induce transient BBB disruption of peri-tumoral brain in patients with recurrent glioblastoma. We found radiographic evidence that BBB integrity was mostly restored within 1-hour of this procedure. Using single-cell RNA sequencing and transmission electron microscopy, we analyzed the acute response of human brain ECs to ultrasound-mediated BBB disruption. Our analysis revealed distinct EC gene expression changes after LIPU/MB, particularly in genes related to neurovascular barrier function and structure, including changes to genes involved in the basement membrane, EC cytoskeleton, and junction complexes, as well as caveolar transcytosis and various solute transporters. Ultrastructural analysis showed that LIPU/MB led to a decrease in luminal caveolae, the emergence of cytoplasmic vacuoles, and the disruption of the basement membrane and tight junctions, among other things. These findings suggested that acute BBB disruption by LIPU/MB led to specific transcriptional and ultrastructural changes and could represent a conserved mechanism of BBB repair after neurovascular injury in humans.
Authors
Andrew Gould, Yu Luan, Ye Hou, Farida V. Korobova, Li Chen, Victor A. Arrieta, Christina Amidei, Rachel Ward, Cristal Gomez, Brandyn Castro, Karl Habashy, Daniel Zhang, Mark Youngblood, Crismita Dmello, John Bebawy, Guillaume Bouchoux, Roger Stupp, Michael Canney, Feng Yue, M. Luisa Iruela-Arispe, Adam M. Sonabend
Abstract
The opioid system plays crucial roles in modulating social behaviors in both humans and animals. However, the pharmacological profiles of opioids regarding social behavior and their therapeutic potential remain unclear. Multiple pharmacological, behavioral, and immunohistological c-Fos mapping approaches were used to characterize the effects of μ-opioid receptor agonists on social behavior and investigate the mechanisms in naive mice and autism spectrum disorder–like (ASD-like) mouse models, such as prenatally valproic acid–treated mice and Fmr1-KO mice. Here, we report that low-dose morphine, a μ-opioid receptor agonist, promoted social behavior by selectively activating neurons in prosocial brain regions, including the nucleus accumbens, but not those in the dorsomedial periaqueductal gray (dmPAG), which are only activated by analgesic high-dose morphine. Critically, intra-dmPAG morphine injection counteracted the prosocial effect of low-dose morphine, suggesting that dmPAG neural activation suppresses social behavior. Moreover, buprenorphine, a μ-opioid receptor partial agonist with less abuse liability and a well-established safety profile, ameliorated social behavior deficits in two mouse models recapitulating ASD symptoms by selectively activating prosocial brain regions without dmPAG neural activation. Our findings highlight the therapeutic potential of brain region–specific neural activation induced by low-dose opioids for social behavior deficits in ASD.
Authors
Soichiro Ohnami, Megumi Naito, Haruki Kawase, Momoko Higuchi, Shigeru Hasebe, Keiko Takasu, Ryo Kanemaru, Yuki Azuma, Rei Yokoyama, Takahiro Kochi, Eiji Imado, Takeru Tahara, Yaichiro Kotake, Satoshi Asano, Naoya Oishi, Kazuhiro Takuma, Hitoshi Hashimoto, Koichi Ogawa, Atsushi Nakamura, Hidekuni Yamakawa, Yukio Ago
Abstract
In the mammalian cochlea, sensory hair cells are crucial for the transduction of acoustic stimuli into electrical signals, which are then relayed to the central auditory pathway via spiral ganglion neuron (SGN) afferent dendrites. The SGN output is directly modulated by inhibitory cholinergic axodendritic synapses from the efferent fibers originating in the superior olivary complex. When the adult cochlea is subjected to noxious stimuli or aging, the efferent system undergoes major rewiring, such that it reestablishes direct axosomatic contacts with the inner hair cells (IHCs), which occur only transiently during prehearing stages of development. The trigger, origin, and degree of efferent plasticity in the cochlea remains largely unknown. Using functional and morphological approaches, we demonstrate that efferent plasticity in the adult cochlea occurs as a direct consequence of mechanoelectrical transducer current dysfunction. We also show that, different from prehearing stages of development, the lateral olivocochlear — but not the medial olivocochlear — efferent fibers are those that form the axosomatic synapses with the IHCs. The study also demonstrates that in vivo restoration of IHC function using AAV-Myo7a rescue reestablishes the synaptic profile of adult IHCs and improves hearing, highlighting the potential of using gene-replacement therapy for progressive hearing loss.
Authors
Andrew P. O’Connor, Ana E. Amariutei, Alice Zanella, Sarah A. Hool, Adam J. Carlton, Fanbo Kong, Mauricio Saenz-Roldan, Jing-Yi Jeng, Marie-José Lecomte, Stuart L. Johnson, Saaid Safieddine, Walter Marcotti
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