In patients with multiple sclerosis (MS) and mice with experimental autoimmune encephalomyelitis (EAE), inflammatory axonal injury is a major determinant of disability; however, the drivers of this injury are incompletely understood. Here, we used the EAE model and determined that the extracellular matrix protein matrilin-2 (MATN2) is an endogenous neuronal molecule that is regulated in association with inflammatory axonal injury. Compared with WT mice, mice harboring a deletion of
Anna Jonas, Stefan Thiem, Tanja Kuhlmann, Raimund Wagener, Attila Aszodi, Cameron Nowell, Karin Hagemeier, Louise Laverick, Victoria Perreau, Vilija Jokubaitis, Ben Emery, Trevor Kilpatrick, Helmut Butzkueven, Melissa Gresle
Cholestenoic acids are formed as intermediates in metabolism of cholesterol to bile acids, and the biosynthetic enzymes that generate cholestenoic acids are expressed in the mammalian CNS. Here, we evaluated the cholestenoic acid profile of mammalian cerebrospinal fluid (CSF) and determined that specific cholestenoic acids activate the liver X receptors (LXRs), enhance islet-1 expression in zebrafish, and increase the number of oculomotor neurons in the developing mouse in vitro and in vivo. While 3β,7α-dihydroxycholest-5-en-26-oic acid (3β,7α-diHCA) promoted motor neuron survival in an LXR-dependent manner, 3β-hydroxy-7-oxocholest-5-en-26-oic acid (3βH,7O-CA) promoted maturation of precursors into islet-1+ cells. Unlike 3β,7α-diHCA and 3βH,7O-CA, 3β-hydroxycholest-5-en-26-oic acid (3β-HCA) caused motor neuron cell loss in mice. Mutations in
Spyridon Theofilopoulos, William J. Griffiths, Peter J. Crick, Shanzheng Yang, Anna Meljon, Michael Ogundare, Satish Srinivas Kitambi, Andrew Lockhart, Karin Tuschl, Peter T. Clayton, Andrew A. Morris, Adelaida Martinez, M. Ashwin Reddy, Andrea Martinuzzi, Maria T. Bassi, Akira Honda, Tatsuki Mizuochi, Akihiko Kimura, Hiroshi Nittono, Giuseppe De Michele, Rosa Carbone, Chiara Criscuolo, Joyce L. Yau, Jonathan R. Seckl, Rebecca Schüle, Ludger Schöls, Andreas W. Sailer, Jens Kuhle, Matthew J. Fraidakis, Jan-Åke Gustafsson, Knut R. Steffensen, Ingemar Björkhem, Patrik Ernfors, Jan Sjövall, Ernest Arenas, Yuqin Wang
Parkinson’s disease (PD) is the most prevalent hypokinetic movement disorder, and symptomatic PD pathogenesis has been ascribed to imbalances between the direct and indirect pathways in the basal ganglia circuitry. Here, we applied glutamate receptor blockers to the subthalamic nucleus (STN) of parkinsonian rats and evaluated locomotor behaviors via single-unit and local-field recordings. Using this model, we found that inhibition of NMDAergic cortico-subthalamic transmission ameliorates parkinsonian motor deficits without eliciting any vivid turning behavior and abolishes electrophysiological abnormalities, including excessive subthalamic bursts, cortico-subthalamic synchronization, and in situ beta synchronization in both the motor cortex and STN. Premotor cortex stimulation revealed that cortico-subthalamic transmission is deranged in PD and directly responsible for the excessive stimulation-dependent bursts and time-locked spikes in the STN, explaining the genesis of PD-associated pathological bursts and synchronization, respectively. Moreover, application of a dopaminergic agent via a microinfusion cannula localized the therapeutic effect to the STN, without correcting striatal dopamine deficiency. Finally, optogenetic overactivation and synchronization of cortico-subthalamic transmission alone sufficiently and instantaneously induced parkinsonian-associated locomotor dysfunction in normal mice. In addition to the classic theory emphasizing the direct-indirect pathways, our data suggest that deranged cortico-subthalamic transmission via the NMDA receptor also plays a central role in the pathophysiology of parkinsonian motor deficits.
Ming-Kai Pan, Chun-Hwei Tai, Wen-Chuan Liu, Ju-Chun Pei, Wen-Sung Lai, Chung-Chin Kuo
Learning and memory deficits are early clinical manifestations of Huntington’s disease (HD). These cognitive impairments have been mainly associated with frontostriatal HD pathology; however, compelling evidence provided by several HD murine models suggests that the hippocampus may contribute to synaptic deficits and memory dysfunction in HD. The neurotrophin receptor p75NTR negatively regulates spine density, which is associated with learning and memory; therefore, we explored whether disturbed p75NTR function in the hippocampus could contribute to synaptic dysfunction and memory deficits in HD. Here, we determined that levels of p75NTR are markedly increased in the hippocampus of 2 distinct mouse models of HD and in HD patients. Normalization of p75NTR levels in HD mutant mice heterozygous for
Verónica Brito, Albert Giralt, Lilian Enriquez-Barreto, Mar Puigdellívol, Nuria Suelves, Alfonsa Zamora-Moratalla, Jesús J. Ballesteros, Eduardo D. Martín, Nuria Dominguez-Iturza, Miguel Morales, Jordi Alberch, Sílvia Ginés
Binge eating afflicts approximately 5% of US adults, though effective treatments are limited. Here, we showed that estrogen replacement substantially suppresses binge-like eating behavior in ovariectomized female mice. Estrogen-dependent inhibition of binge-like eating was blocked in female mice specifically lacking estrogen receptor-α (ERα) in serotonin (5-HT) neurons in the dorsal raphe nuclei (DRN). Administration of a recently developed glucagon-like peptide-1–estrogen (GLP-1–estrogen) conjugate designed to deliver estrogen to GLP1 receptor–enhanced regions effectively targeted bioactive estrogens to the DRN and substantially suppressed binge-like eating in ovariectomized female mice. Administration of GLP-1 alone reduced binge-like eating, but not to the same extent as the GLP-1–estrogen conjugate. Administration of ERα-selective agonist propylpyrazole triol (PPT) to murine DRN 5-HT neurons activated these neurons in an ERα-dependent manner. PPT also inhibited a small conductance Ca2+-activated K+ (SK) current; blockade of the SK current prevented PPT-induced activation of DRN 5-HT neurons. Furthermore, local inhibition of the SK current in the DRN markedly suppressed binge-like eating in female mice. Together, our data indicate that estrogens act upon ERα to inhibit the SK current in DRN 5-HT neurons, thereby activating these neurons to suppress binge-like eating behavior and suggest ERα and/or SK current in DRN 5-HT neurons as potential targets for anti-binge therapies.
Xuehong Cao, Pingwen Xu, Mario G. Oyola, Yan Xia, Xiaofeng Yan, Kenji Saito, Fang Zou, Chunmei Wang, Yongjie Yang, Antentor Hinton Jr., Chunling Yan, Hongfang Ding, Liangru Zhu, Likai Yu, Bin Yang, Yuxin Feng, Deborah J. Clegg, Sohaib Khan, Richard DiMarchi, Shaila K. Mani, Qingchun Tong, Yong Xu
The transmission of pruritoceptive (itch) messages involves specific neural circuits within the spinal cord that are distinct from those that transmit pain messages. These itch-specific circuits are tonically regulated by inhibitory interneurons in the dorsal horn. Consistent with these findings, it has previously been reported that loss of GABAergic interneurons in mice harboring a deletion of the transcription factor
Joao M. Braz, Dina Juarez-Salinas, Sarah E. Ross, Allan I. Basbaum
Parkinsonism and attention deficit hyperactivity disorder (ADHD) are widespread brain disorders that involve disturbances of dopaminergic signaling. The sodium-coupled dopamine transporter (DAT) controls dopamine homeostasis, but its contribution to disease remains poorly understood. Here, we analyzed a cohort of patients with atypical movement disorder and identified 2 DAT coding variants, DAT-Ile312Phe and a presumed de novo mutant DAT-Asp421Asn, in an adult male with early-onset parkinsonism and ADHD. According to DAT single-photon emission computed tomography (DAT-SPECT) scans and a fluoro-deoxy-glucose-PET/MRI (FDG-PET/MRI) scan, the patient suffered from progressive dopaminergic neurodegeneration. In heterologous cells, both DAT variants exhibited markedly reduced dopamine uptake capacity but preserved membrane targeting, consistent with impaired catalytic activity. Computational simulations and uptake experiments suggested that the disrupted function of the DAT-Asp421Asn mutant is the result of compromised sodium binding, in agreement with Asp421 coordinating sodium at the second sodium site. For DAT-Asp421Asn, substrate efflux experiments revealed a constitutive, anomalous efflux of dopamine, and electrophysiological analyses identified a large cation leak that might further perturb dopaminergic neurotransmission. Our results link specific DAT missense mutations to neurodegenerative early-onset parkinsonism. Moreover, the neuropsychiatric comorbidity provides additional support for the idea that DAT missense mutations are an ADHD risk factor and suggests that complex DAT genotype and phenotype correlations contribute to different dopaminergic pathologies.
Freja H. Hansen, Tina Skjørringe, Saiqa Yasmeen, Natascha V. Arends, Michelle A. Sahai, Kevin Erreger, Thorvald F. Andreassen, Marion Holy, Peter J. Hamilton, Viruna Neergheen, Merete Karlsborg, Amy H. Newman, Simon Pope, Simon JR. Heales, Lars Friberg, Ian Law, Lars H. Pinborg, Harald H. Sitte, Claus Loland, Lei Shi, Harel Weinstein, Aurelio Galli, Lena E. Hjermind, Lisbeth B. Møller, Ulrik Gether
Subpopulations of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) display a differential vulnerability to loss in Parkinson’s disease (PD); however, it is not clear why these subsets are preferentially selected in PD-associated neurodegeneration. In rodent SNpc, DA neurons can be divided into two subpopulations based on the expression of aldehyde dehydrogenase 1 (ALDH1A1). Here, we have shown that, in α-synuclein transgenic mice, a murine model of PD-related disease, DA neurodegeneration occurs mainly in a dorsomedial ALDH1A1-negative subpopulation that is also prone to cytotoxic aggregation of α-synuclein. Notably, the topographic ALDH1A1 pattern observed in α-synuclein transgenic mice was conserved in human SNpc. Postmortem evaluation of brains of patients with PD revealed a severe reduction of ALDH1A1 expression and neurodegeneration in the ventral ALDH1A1-positive DA subpopulations. ALDH1A1 expression was also suppressed in α-synuclein transgenic mice. Deletion of
Guoxiang Liu, Jia Yu, Jinhui Ding, Chengsong Xie, Lixin Sun, Iakov Rudenko, Wang Zheng, Namratha Sastry, Jing Luo, Gay Rudow, Juan C. Troncoso, Huaibin Cai
In humans, pruritus (itch) is a common but poorly understood symptom in numerous skin and systemic diseases. Endothelin 1 (ET-1) evokes histamine-independent pruritus in mammals through activation of its cognate G protein–coupled receptor endothelin A receptor (ETAR). Here, we have identified neural endothelin–converting enzyme 1 (ECE-1) as a key regulator of ET-1–induced pruritus and neural signaling of itch. We show here that ETAR, ET-1, and ECE-1 are expressed and colocalize in murine dorsal root ganglia (DRG) neurons and human skin nerves. In murine DRG neurons, ET-1 induced internalization of ETAR within ECE-1–containing endosomes. ECE-1 inhibition slowed ETAR recycling yet prolonged ET-1–induced activation of ERK1/2, but not p38. In a murine itch model, ET-1–induced scratching behavior was substantially augmented by pharmacological ECE-1 inhibition and abrogated by treatment with an ERK1/2 inhibitor. Using iontophoresis, we demonstrated that ET-1 is a potent, partially histamine-independent pruritogen in humans. Immunohistochemical evaluation of skin from prurigo nodularis patients confirmed an upregulation of the ET-1/ETAR/ECE-1/ERK1/2 axis in patients with chronic itch. Together, our data identify the neural peptidase ECE-1 as a negative regulator of itch on sensory nerves by directly regulating ET-1–induced pruritus in humans and mice. Furthermore, these results implicate the ET-1/ECE-1/ERK1/2 pathway as a therapeutic target to treat pruritus in humans.
Makiko Kido-Nakahara, Jörg Buddenkotte, Cordula Kempkes, Akihiko Ikoma, Ferda Cevikbas, Tasuku Akiyama, Frank Nunes, Stephan Seeliger, Burcu Hasdemir, Christian Mess, Timo Buhl, Mathias Sulk, Frank-Ulrich Müller, Dieter Metze, Nigel W. Bunnett, Aditi Bhargava, Earl Carstens, Masutaka Furue, Martin Steinhoff
Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3β (GSK3β) in nerves of mutant mice. Treatment with GSK3β inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling.
Tiago Ferreira da Silva, Jessica Eira, André T. Lopes, Ana R. Malheiro, Vera Sousa, Adrienne Luoma, Robin L. Avila, Ronald J.A. Wanders, Wilhelm W. Just, Daniel A. Kirschner, Mónica M. Sousa, Pedro Brites