Neuroscience
Abstract
Although a disease-modifying therapy for CLN2 disease now exists, a poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients, but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities including spontaneous seizures, providing a robust and quantifiable disease-relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord, and differs markedly from the staging seen in mouse models of other forms of NCL. Neonatal administration of adeno-associated virus 9 (AAV9)-mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the lifespan of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging pre-clinical efficacy of therapeutic interventions for CLN2 disease.
Authors
Keigo Takahashi, Elizabeth M. Eultgen, Sophie H. Wang, Nicholas R. Rensing, Hemanth R. Nelvagal, Joshua T. Dearborn, Olivier Danos, Nicholas Buss, Mark S. Sands, Michael Wong, Jonathan D. Cooper
Abstract
Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH wild-type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contribute to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures are often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, D-2-hydroxyglutarate, rapidly synchronizes neuronal spike firing in a seizure-like manner, but only when nonneoplastic glial cells are present. In vitro and in vivo models can recapitulate IDHmut glioma-associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibit seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.
Authors
Michael Drumm, Wenxia Wang, Thomas K. Sears, Kirsten Bell-Burdett, Rodrigo Javier, Kristen Y. Cotton, Brynna T. Webb, Kayla T. Byrne, Dusten Unruh, Vineeth Thirunavu, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Rimas V. Lukas, Joanna J. Phillips, Esraa Mohamed, John D. Finan, Lucas Santana-Santos, Amy B. Heimberger, Colin K. Franz, Jonathan E. Kurz, Jessica W. Templer, Geoffrey T. Swanson, Craig Horbinski
Abstract
Neuropathic pain remains poorly managed by current therapies highlighting the need to improve our knowledge of chronic pain mechanisms. In neuropathic pain models, dorsal root ganglia (DRG) nociceptive neurons transfer miR-21 packaged in extracellular vesicles to macrophages that promote pro-inflammatory phenotype and contribute to allodynia. Here we show that miR-21 conditional deletion in DRG neurons was coupled with lack of up-regulation of CCL2 chemokine after nerve injury and reduced accumulation of CCR2-expressing macrophages, which showed TGFB-related pathway activation and acquired M2-like anti-nociceptive phenotype. Indeed, neuropathic allodynia was attenuated in cKO and restored by a TGFB receptor inhibitor (SB431542) administration. Since TGFBR2 and TGFB1 are known miR-21 targets, we suggest that miR-21 transfer from injured neurons to macrophages maintains a pro-inflammatory phenotype via suppression of such an anti-inflammatory pathway. These data support miR-21 inhibition as a possible approach to maintain polarization of DRG macrophages at M2-like state and attenuate neuropathic pain.
Authors
Lynda Zeboudj, George Sideris-Lampretsas, Rita Silva, Sabeha Al-Mudaris, Francesca Picco, Sarah Fox, David Chambers, Marzia Malcangio
Abstract
Authors
Kara N. Thomas, Nimisha Srikanth, Sanat S. Bhadsavle, Kelly R. Thomas, Katherine N. Zimmel, Alison Basel, Alexis N. Roach, Nicole A. Mehta, Yudhishtar S. Bedi, Michael C. Golding
Abstract
Despite advances in acute care, ischemic stroke remains a major cause of long-term disability. Approaches targeting both neuronal and glial responses are needed to enhance recovery and improve long-term outcome. The complement C3a receptor (C3aR) is a regulator of inflammation with roles in neurodevelopment, neural plasticity, and neurodegeneration. Using mice lacking C3aR (C3aR–/–) and mice overexpressing C3a in the brain, we uncovered two opposing effects of C3aR signaling on functional recovery after ischemic stroke: inhibition in the acute phase and facilitation in the later phase. Peri-infarct astrocyte reactivity was increased and density of microglia reduced in C3aR–/– mice, C3a overexpression led to the opposite effects. Pharmacological treatment of wild-type mice with intranasal C3a starting 7 days after stroke accelerated recovery of motor function and attenuated astrocyte reactivity without enhancing microgliosis. C3a treatment stimulated global white matter reorganization, increased peri-infarct structural connectivity and upregulated Igf1 and Thbs4 in the peri-infarct cortex. Thus, C3a treatment from day 7 after stroke exerts positive effects on astrocytes and neuronal connectivity while avoiding the deleterious consequences of C3aR signaling during the acute phase. Intranasal administration of C3aR agonists within convenient time window holds translational promise to improve outcome after ischemic stroke.
Authors
Anna Stokowska, Markus Aswendt, Daniel Zucha, Stephanie Lohmann, Frederique Wieters, Javier Moran Suarez, Alison L. Atkins, YiXian Li, Maria Miteva, Julia Lewin, Dirk Wiedermann, Michael Diedenhofen, Åsa Torinsson Naluai, Pavel Abaffy, Lukas Valihrach, Mikael Kubista, Mathias Hoehn, Milos Pekny, Marcela Pekna
Abstract
Spastic paraplegia 50 (SPG50) is an ultrarare childhood-onset neurological disorder caused by biallelic loss-of-function variants in the AP4M1 gene. SPG50 is characterized by progressive spastic paraplegia, global developmental delay and subsequent intellectual disability, secondary microcephaly, and epilepsy. Preclinical studies evaluated an adeno-associated virus (AAV)/AP4M1 gene therapy for SPG50. In vitro studies demonstrated that transduction of patient-derived fibroblasts with AAV2/AP4M1 resulted in phenotypic rescue. To evaluate efficacy in vivo, Ap4m1 knockout mice were intrathecally (IT) injected with 5E11, 2.5E11, or 1.25E11 vg doses of AAV9/AP4M1 at postnatal day p7-10 (pre-manifesting cohorts) or p90 (early manifesting cohorts). Age- and dose-dependent effects were observed, with early intervention and higher doses achieving the best therapeutic benefits. In parallel, three toxicology studies in wild-type mice, rats, and non-human primates (NHPs) demonstrated that AAV9/AP4M1 had an acceptable safety profile up to a target human dose of 1E15 vg. Of note, similar degrees of minimal to mild dorsal root ganglia (DRG) toxicity were observed in both rats and NHPs, supporting the use of rats to monitor DRG toxicity in future IT AAV studies. These preclinical results identify an acceptably safe and efficacious dose of IT-administered AAV9/AP4M1, supporting an investigational gene transfer clinical trial to treat SPG50.
Authors
Xin Chen, Thomas Dong, Yuhui Hu, Raffaella De Pace, Rafael Mattera, Kathrin Eberhardt, Marvin Ziegler, Terry Pirovolakis, Mustafa Sahin, Juan S. Bonifacino, Darius Ebrahimi-Fakhari, Steven J. Gray
Abstract
Sphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental to cancer, best exemplified in the inborn errors of sphingolipid metabolism in lysosomes. The dihydroceramide desaturase DEGS1 acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18, OMIM #618404). Here, we reveal that DEGS1 is a mitochondria-associated endoplasmic reticulum membrane (MAM)-resident enzyme, refining previous reports locating DEGS1 at the endoplasmic reticulum only. Using patient fibroblasts, multi-omics and enzymatic assays, we show that DEGS1 deficiency disrupts the main core functions of the MAM: i) mitochondrial dynamics, with a hyperfused mitochondrial network associated with decreased activation of dynamin-related protein 1; ii) cholesterol metabolism, with impaired sterol O-acyltransferase activity and decreased cholesteryl esters; iii) phospholipid metabolism, with increased phosphatidic acid and phosphatidylserine and decreased phosphatidylethanolamine; iv) biogenesis of lipid droplets, with increased size and numbers. Moreover, we detected increased mitochondrial superoxide species production in fibroblasts and mitochondrial respiration impairment in patient muscle biopsy tissues. Our findings shed light on the pathophysiology of HLD18 and broaden our understanding of the role of sphingolipid metabolism in MAMs function.
Authors
Laura Planas-Serra, Nathalie Launay, Leire Goicoechea, Bénédicte Heron, Cristina Jou, Natalia Juliá-Palacios, Montserrat Ruiz, Stéphane Fourcade, Carlos Casasnovas, Carolina De La Torre, Antoinette Gelot, Maria Marsal, Pablo Loza-Alvarez, Àngels García-Cazorla, Ali Fatemi, Isidre Ferrer, Manuel Portero-Otin, Estela Area-Gómez, Aurora Pujol
Abstract
Peripheral neuropathy is a frequent complication of type 2 diabetes mellitus (T2DM). We investigated whether human islet amyloid polypeptide (hIAPP), which forms pathogenic aggregates that damage pancreatic islet β-cells in T2DM, is involved in T2DM-associated peripheral neuropathy. In vitro, hIAPP incubation with sensory neurons reduced neurite outgrowth and increased levels of mitochondrial reactive oxygen species. Transgenic hIAPP mice that have elevated plasma hIAPP levels without hyperglycemia developed peripheral neuropathy as evidenced by pain-associated behavior and reduced intra-epidermal nerve fiber (IENF) density. Similarly, hIAPP Ob/Ob mice that have hyperglycaemia in combination with elevated plasma hIAPP levels had signs of neuropathy, although more aggravated.In wild-type mice, intraplantar and intravenous hIAPP injections induced long-lasting allodynia and decreased IENF density. Non-aggregating murine IAPP, mutated hIAPP (Pramlintide), or hIAPP with pharmacologically inhibited aggregation did not induce these effects. T2DM patients had reduced IENF density and more hIAPP oligomers in the skin compared to non-T2DM controls. Thus, we provide evidence that hIAPP aggregation is neurotoxic and mediates peripheral neuropathy in mice. The increased abundance of hIAPP aggregates in the skin of T2DM patients supports the notion that hIAPP is a potential contributor to T2DM neuropathy in humans.
Authors
Mohammed M.H. Albariqi, Sabine Versteeg, Elisabeth M. Brakkee, J. Henk Coert, Barend O.W. Elenbaas, Judith Prado, C. Erik Hack, Jo W.M. Höppener, Niels Eijkelkamp
Abstract
Chronic pain could cause both hyperalgesia and anxiety symptoms. How the two components are encoded in the brain remains unclear. The prelimbic cortex (PrL), a critical brain region for both nociceptive and emotional modulations, serves as an ideal medium for comparing the encoding of the two components. We report that PrL neurons projecting to the basolateral amygdala (PrLBLA) and those projecting to the ventrolateral periaqueductal gray (PrLl/vlPAG) were segregated and displayed elevated and reduced neuronal activity, respectively, during pain chronicity. Consistently, optogenetic suppression of PrL→BLA circuit reversed anxiety-like behaviors whereas activation of PrL→l/vlPAG circuit attenuated hyperalgesia in mice with chronic pain. Moreover, mechanistic studies indicated that elevated TNF-α/TNFR1 signaling in PrL caused increased insertion of GluA1 receptors into PrLBLA neurons contributing to anxiety-like behaviors in mice with chronic pain. Together, these results provide insights into the circuit and molecular mechanisms in PrL for controlling pain-related hyperalgesia and anxiety-like behaviors.
Authors
Feng Gao, Jie Huang, Guo-Bin Huang, Qiang-Long You, Shan Yao, Shen-Ting Zhao, Jian Liu, Cui-Hong Wu, Gui-Fu Chen, Shi-Min Liu, Zongyan Yu, Yan-Ling Zhou, Yu-Ping Ning, Shenquan Liu, Bing-Jie Hu, Xiang-Dong Sun
Abstract
The spatiotemporal pattern of the spread of pathologically modified tau through brain regions in Alzheimer’s disease (AD) can be explained by prion-like cell-to-cell seeding and propagation of misfolded tau aggregates. Hence, to develop targeted therapeutic antibodies, it is important to identify the seeding- and propagation-competent tau species. The hexapeptide 275VQIINK280 of tau is a critical region for tau aggregation, and K280 is acetylated in various tauopathies including AD. However, the mechanism that links tau acetylated on lysine 280 (tau-acK280) to subsequent progression to neurodegenerative disease remains unclear. Here, we demonstrate that tau-acK280 is critical for tau propagation processes including secretion, aggregation, and seeding. We developed an antibody, Y01, that specifically targets tau-acK280 and solved the crystal structure of Y01 in complex with an acK280 peptide. The structure confirmed that Y01 directly recognizes acK280 and the surrounding residues. Strikingly, upon interaction with acetylated tau aggregates, Y01 prevented tauopathy progression and increased neuronal viability in neuron cultures and in tau transgenic mice through antibody-mediated neutralization and phagocytosis, respectively. Based on our observations that tau-acK280 is a core species involved in seeding and propagation activities, the Y01 antibody that specifically recognizes acK280 represents a promising therapeutic candidate for AD and other neurodegenerative diseases associated with tauopathy.
Authors
Ha-Lim Song, Na-Young Kim, Jaewan Park, Meong Il Kim, Yu-Na Jeon, Se-Jong Lee, Kwangmin Cho, Young-Lim Shim, Kyoung-Hye Lee, Yeon-Seon Mun, Jung-A Song, Min-Seok Kim, Chan-Gi Pack, Minkyo Jung, Hyemin Jang, Duk L. Na, Minsun Hong, Dong-Hou Kim, Seung-Yong Yoon
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)