Neuroscience
Abstract
Gestational hypertension (GH) is prevalent, with life-long health burdens for mothers and their children exposed in utero. We analyzed the nation-wide Epic Cosmos dataset and found significantly higher rates of seizures in children of mothers with GH than in children of normotensive mothers. Complementary studies of nested Iowa and Stanford cohorts and a large Taiwanese cohort also revealed significantly increased seizure risk after covariate adjustments. We modeled this association in an angiotensin (ANG) II mouse model of GH. Maternal ANG II significantly increased seizure grade and deaths elicited by pilocarpine among male but not female offspring. Electrical stimulation increased seizure grade and death across sexes in offspring from ANG II–treated dams. Proinflammatory and microglial gene expression in the brain were upregulated only in male offspring from ANG II–treated dams. Chronic phenylephrine, a GH model lacking the maternal proinflammatory aspects of ANG II, induced similar offspring seizure phenotypes. PLX5622-induced depletion of microglia or antiinflammatory pentoxifylline abolished this sensitized seizure response and lowered mortality in the ANG II model. These results suggest that GH programs offspring risk for seizures in a sex-dependent manner in humans and mice. Neuroinflammatory mechanisms may contribute to the elevated sensitivity and mortality from seizures elicited by GH exposure in utero.
Authors
Baojian Xue, Serena B. Gumusoglu, Grant Tiarks, Brittany P. Todd, Angela Wong, Donna A. Santillan, Chin-Chi Kuo, Hsiu-Yin Chiang, Rohith Ravindranath, Sophia Y. Wang, Vinit B. Mahajan, Alan Kim Johnson, Heath A. Davis, Polly Ferguson, Elizabeth A. Newell, Mark K. Santillan, Jason M. Misurac, Alexander G. Bassuk
MuSK cysteine-rich domain antibodies are pathogenic in a mouse model of autoimmune myasthenia gravis
Abstract
The neuromuscular junction (NMJ), synapse between the motor neuron terminal and a skeletal muscle fiber is crucial, throughout life, in maintaining the reliable neurotransmission required for functional motricity. Disruption of this system leads to neuromuscular disorders, such as auto-immune myasthenia gravis (MG), the most common form of NMJ diseases. MG is caused by autoantibodies directed mostly against the acetylcholine receptor (AChR) or the muscle-specific kinase MuSK. Several studies report immunoreactivity to the Frizzled-like cysteine-rich Wnt-binding domain of MuSK (CRD) in patients, although the pathogenicity of the antibodies involved remains unknown. We showed here that the immunoreactivity to MuSK CRD induced by the passive transfer of anti-MuSKCRD antibodies in mice led to typical MG symptoms, characterized by a loss of body weight and a locomotor deficit. The functional and morphological integrity of the NMJ was compromised with a progressive decay of neurotransmission and disruption of the structure of pre- and post-synaptic compartments. We found that anti-MuSKCRD antibodies completely abolished Agrin-mediated AChR clustering by decreasing the Lrp4-MuSK interaction. These results provide the first demonstration of the role of the MuSK CRD in MG pathogenesis and improve our understanding of the underlying pathophysiological mechanisms.
Authors
Marius Halliez, Steve Cottin, Axel You, Céline Buon, Antony Grondin, Léa S. Lippens, Megane Lemaitre, Jérome Ezan, Charlotte Isch, Yann Rufin, Mireille Montcouquiol, Nathalie Sans, Bertrand Fontaine, Julien Messéant, Rozen Le Panse, Laure Strochlic
Abstract
Authors
Nishanth S. Sadagopan, Rushmin Khazanchi, Rishi Jain, Amy B. Heimberger, Stephen T. Magill
Abstract
Abnormal expansions of CAG trinucleotide repeat within specific gene exons give rise to polyglutamine (polyQ) diseases, a family of inherited disorders characterized by late-onset neurodegeneration. Recently, a new type of polyQ disease was identified and named spinocerebellar ataxia 51 (SCA51). SCA51 is caused by polyQ expansion in THAP11, an essential transcription factor for brain development. The pathogenesis of SCA51, particularly how mutant THAP11 with polyQ expansion contributes to neuropathology, remains elusive. Our study of mouse and monkey brains revealed that THAP11 expression is subject to developmental regulation, showing enrichment in the cerebellum. However, knocking down endogenous THAP11 in adult mice does not affect neuronal survival. In contrast, expressing mutant THAP11 with polyQ expansion leads to pronounced protein aggregation, cerebellar neurodegeneration, and motor deficits, indicating that gain-of-function mechanisms are central to SCA51 pathogenesis. We discovered activated microglia expressing TREM2 in the cerebellum of a newly developed SCA51 knock-in mouse model. Mechanistically, mutant THAP11 enhances the transcription of TREM2, leading to its upregulation. The loss of TREM2 or depletion of microglia mitigates neurodegeneration induced by mutant THAP11. Our study offers the first mechanistic insights into the pathogenesis of SCA51, highlighting the role of TREM2-mediated microglial activation in SCA51 neuropathology.
Authors
Eshu Ruan, Jingpan Lin, Zhao Chen, Qianai Sheng, Laiqiang Chen, Jiating He, Xuezhi Duan, Yiyang Qin, Tingting Xing, Sitong Yang, Mingtian Pan, Xiangyu Guo, Peng Yin, Xiao-Jiang Li, Hong Jiang, Shihua Li, Su Yang
Abstract
Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43) are observed in many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TDP-43 dysregulation of splicing has emerged as a key event in these diseases, TDP-43 can also regulate polyadenylation; yet this has not been adequately studied. Here, we applied the dynamic analysis of polyadenylation from an RNA-Seq (DaPars) tool to ALS/FTD transcriptome datasets and report extensive alternative polyadenylation (APA) upon TDP-43 alteration in ALS/FTD cell models and postmortem ALS/FTD neuronal nuclei. Importantly, many identified APA genes highlight pathways implicated in ALS/FTD pathogenesis. To determine the functional relevance of APA elicited by TDP-43 nuclear depletion, we examined microtubule affinity regulating kinase 3 (MARK3). Nuclear loss of TDP-43 yielded increased expression of MARK3 transcripts with longer 3′ UTRs, corresponding with a change in the subcellular distribution of MARK3 and increased neuronal tau S262 phosphorylation. Our findings define changes in polyadenylation site selection as a previously understudied feature of TDP-43–driven disease pathology in ALS/FTD and highlight a potentially important mechanistic link between TDP-43 dysfunction and tau regulation.
Authors
Frederick J. Arnold, Ya Cui, Sebastian Michels, Michael R. Colwin, Cameron M. Stockford, Wenbin Ye, Vidhya Maheswari Jawahar, Karen Jansen-West, Julien Philippe, Ravinder Gulia, Yunzi Gou, Oliver H. Tam, Sneha Menon, Wendy G. Situ, Saira L. Cazarez, Aryan Zandi, Kean C.K. Ehsani, Sierra Howard, Dennis W. Dickson, Molly Gale Hammell, Mercedes Prudencio, Leonard Petrucelli, Wei Li, Albert R. La Spada
Abstract
Spinal microglia play a pivotal role in the development of neuropathic pain. Peripheral nerve injury induces changes in the transcriptional profile of microglia, including increased expression of components of the translational machinery. Whether microglial protein synthesis is stimulated following nerve injury and has a functional role in mediating pain hypersensitivity is unknown. Here, we show that nascent protein synthesis is upregulated in spinal microglia following peripheral nerve injury in both male and female mice. Stimulating mRNA translation in microglia by selectively ablating the translational repressor eukaryotic initiation factor 4E–binding protein 1 (4E-BP1) promoted the transition of microglia to a reactive state and induced mechanical hypersensitivity in both sexes, whereas spontaneous pain was increased only in males. Conversely, inhibiting microglial translation by expressing a mutant form of 4E-BP1 in microglia attenuated their activation following peripheral nerve injury and alleviated neuropathic pain in both sexes. Thus, stimulating 4E-BP1–dependent translation promotes microglial reactivity and mechanical hypersensitivity, whereas inhibiting it alleviates neuropathic pain.
Authors
Kevin C. Lister, Calvin Wong, Weihua Cai, Sonali Uttam, Patricia Stecum, Rose Rodrigues, Mehdi Hooshmandi, Nicole Brown, Jonathan Fan, Noe Francois-Saint-Cyr, Shannon Tansley, Volodya Hovhannisyan, Diana Tavares-Ferreira, Nikhil Nageshwar Inturi, Khadijah Mazhar, Alain Pacis, Jieyi Yang, Alfredo Ribeiro-da-Silva, Christos G. Gkogkas, Theodore J. Price, Jeffrey S. Mogil, Arkady Khoutorsky
Abstract
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS. Clemastine fumarate, the over-the-counter antihistamine and muscarinic receptor blocker, has remyelinating potential in MS. A clemastine arm was added to an ongoing platform clinical trial, targeting residual activity by precision, biomarker-guided combination therapies of multiple sclerosis (TRAP-MS) (ClinicalTrials.gov NCT03109288), to identify a cerebrospinal fluid (CSF) remyelination signature and to collect safety data on clemastine in patients progressing independently of relapse activity (PIRA). The clemastine arm was stopped per protocol-defined criteria when 3 of 9 patients triggered individual safety stopping criteria. Clemastine-treated patients had significantly higher treatment-induced disability progression slopes compared with the remaining TRAP-MS participants. Quantification of approximately 7,000 proteins in CSF samples collected before and after clemastine treatment showed significant increases in purinergic signaling and pyroptosis. Mechanistic studies showed that clemastine with sublytic doses of extracellular adenosine triphosphate (ATP) activates inflammasome and induces pyroptotic cell death in macrophages. Clemastine with ATP also caused pyroptosis of induced pluripotent stem cell–derived human oligodendrocytes. Antagonist of the purinergic channel P2RX7, which is strongly expressed in oligodendrocytes and myeloid cells, blocked these toxic effects of clemastine. Finally, reanalysis of published single-nucleus RNA-Seq (snRNA-Seq) studies revealed increased P2RX7 expression and pyroptosis transcriptional signature in microglia and oligodendrocytes in the MS brain, especially in chronic active lesions. The CSF proteomic pyroptosis score was increased in untreated MS patients, was higher in patients with progressive than relapsing-remitting disease, and correlated significantly with the rates of MS progression. Collectively, this identifies pyroptosis as a likely mechanism of CNS injury underlying PIRA even outside of clemastine toxicity.
Authors
Joanna Kocot, Peter Kosa, Shinji Ashida, Nicolette A. Pirjanian, Raphaela Goldbach-Mansky, Karin Peterson, Valentina Fossati, Steven M. Holland, Bibiana Bielekova
Abstract
Accumulating evidence implicates the gut microbiome (GMB) in the pathogenesis and progression of Alzheimer’s disease (AD). We recently showed that the GMB regulates reactive astrocytosis and Aβ plaque accumulation in male APPPS1-21 AD model mice. Yet, the mechanism(s) by which GMB perturbation alters reactive astrocytosis in a manner that reduces Aβ deposition remain unknown. Here, we performed metabolomics on plasma from mice treated with antibiotics (abx) and identified a significant increase in plasma propionate, a gut-derived short chain fatty acid, only in male mice. Administration of sodium propionate reduced reactive astrocytosis and Aβ plaques in APPPS1-21 mice, phenocopying the abx-induced phenotype. Astrocyte-specific RNA sequencing on abx and propionate treated mice showed reduced expression of pro-inflammatory and increased expression of neurotrophic genes. Next, we performed flow cytometry experiments where we found abx and propionate decreased peripheral RAR-related orphan receptor-γ (Rorγt)+ CD4+ (Th17) cells and IL-17 secretion, which positively correlated with reactive astrocytosis. Lastly, using an IL-17 monoclonal antibody to deplete IL-17, we found that propionate reduces reactive astrocytosis and Aβ plaques in an IL-17-dependent manner. Together, these results suggest that gut-derived propionate regulates reactive astrocytosis and Aβ amyloidosis by decreasing peripheral Th17 cells and IL-17 release. Thus, propionate treatment or strategies boosting propionate production may represent novel therapeutic strategies for AD.
Authors
Sidhanth Chandra, Jelena Popovic, Naveen K. Singhal, Elyse A. Watkins, Hemraj B. Dodiya, Ian Q. Weigle, Miranda A. Salvo, Abhirami Ramakrishnan, Zhangying Chen, James T. Watson, Aashutosh Shetti, Natalie Piehl, Xiaoqiong Zhang, Leah K. Cuddy, Katherine R. Sadleir, Steven J. Schwulst, Murali Prakriya, David Gate, Sangram S. Sisodia, Robert Vassar
Abstract
Autosomal Dominant Optic Atrophy (ADOA), the most prevalent hereditary optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the OPA1 gene, which encodes a conserved GTPase important for mitochondrial inner membrane dynamics. To date, the disease mechanism remains unclear, and no therapies are available. We generated a mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulated key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identified SARM1, a neurodegeneration switch, as a key driver of RGC degeneration in these mice. Sarm1 knockout nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation. Additionally, we showed that a portion of SARM1 localized within the mitochondrial intermembrane space (IMS). These findings indicated that SARM1 was activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.
Authors
Chen Ding, Papa S. Ndiaye, Sydney R. Campbell, Michelle Y. Fry, Jincheng Gong, Sophia R. Wienbar, Whitney Gibbs, Philippe Morquette, Luke H. Chao, Michael Tri H. Do, Thomas Schwarz
Abstract
Phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, is a common cause of intellectual disability. However, the mechanisms by which elevated phenylalanine (Phe) levels cause cognitive impairment remain unclear. Here, we show that submillimolar Phe perturbs synaptic plasticity through the hyperactivation of GluN2B-containing NMDARs. PahEnu2 PKU model mice exhibited submillimolar and supramillimolar concentrations of Phe in the cerebrospinal fluid (CSF) and serum, respectively. L-Phe produced concentration-dependent bidirectional effects on NMDA-induced currents, without affecting synaptic NMDARs in hippocampal CA1 neurons. L-Phe-induced hyperactivation of extrasynaptic GluN2B resulted in activity-dependent downregulation of AMPARs during burst or sustained synaptic activity. Administration of L-Phe in mice decreased neural activity and impaired memory, which were blocked by pretreatment with GluN2B inhibitors. Furthermore, pharmacological and virus-mediated suppression of GluN2B reversed the impaired learning in PahEnu2 mice. Collectively, these results suggest that the concentration of Phe in the CSF of patients with PKU perturbs extrasynaptic NMDARs and synaptic plasticity, and that suppression of GluN2B may have the potential to improve cognitive function in patients with PKU.
Authors
Woo Seok Song, Young Sook Kim, Young-Soo Bae, Sang Ho Yoon, Jae Min Lim, Myoung-Hwan Kim
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)