Neuroscience
Abstract
Background: Our objective is to investigate whether primary Sjogren’s syndrome (pSS) is associated with multiple system atrophy (MSA). Methods: We performed a retrospective cohort study assessing rates of (a) MSA in a cohort of patients with pSS, and (b) and rates of pSS in a cohort of patients with MSA. These data were, compared to rates in respective control groups. We additionally reviewed the neuropathologic findings in two patients with pSS, cerebellar degeneration, parkinsonism, and autonomic dysfunction. Results: Our cohort of 308 pSS patients had a greater incidence of MSA compared with four large population-based studies and had had a significantly higher prevalence of at least probable MSA (1% vs. 0%, p = 0.02) compared to 776 patients in a control cohort of patients with other autoimmune disorders. Our cohort of 26 autopsy-proven MSA patients had a significantly higher prevalence of pSS compared with a cohort of 115 patients with other autopsy-proven neurodegenerative disorders (8% vs. 0%, p = 0.03). The two patients we described with pSS and progressive neurodegenerative disease showed classic MSA pathology at autopsy. Conclusion: Our findings provide evidence for an association between MSA and pSS that is specific to both pSS, among autoimmune disorders, and MSA, among neurodegenerative disorders. The two cases we describe of autopsy-proven MSA support that MSA pathology can explains neurologic disease in a subset of pSS patients. These findings together support the hypothesis that systemic autoimmune disease plays role in neurodegeneration. Study funding: The Michigan Brain Bank is supported in part through an NIH grant P30AG053760.
Authors
Kyle S. Conway, Sandra Camelo-Piragua, Amanda O. Fisher-Hubbard, William Perry, Vikram G. Shakkottai, Sriram Venneti
Abstract
Evidence has mounted that insulin can be synthesized in various brain regions including the hypothalamus. However, the distribution and functions of insulin-expressing cells in the hypothalamus remain elusive. Herein, we show that in the mouse hypothalamus, the perikarya of insulin-positive neurons are located in the paraventricular nucleus (PVN) and their axons project to the median eminence; these findings define parvocellular neurosecretory PVN insulin neurons. Contrary to corticotrophin-releasing hormone expression, insulin expression in the PVN was inhibited by restraint stress (RS) in both adult and young mice. Acute RS–induced inhibition of PVN insulin expression in adult mice decreased both pituitary growth hormone (GH) mRNA level and serum GH concentration, which were attenuated by overexpression of PVN insulin. Notably, PVN insulin knockdown or chronic RS in young mice hindered normal growth via the down-regulation of GH gene expression and secretion, whereas PVN insulin overexpression in young mice prevented chronic RS–induced growth retardation by elevating GH production. Our results suggest that in both normal and stressful conditions, insulin synthesized in the parvocellular PVN neurons plays an important role in the regulation of pituitary GH production and body length, unveiling a physiological function of brain-derived insulin.
Authors
Jaemeun Lee, Kyungchan Kim, Jae Hyun Cho, Jin Young Bae, Timothy P. O’Leary, James D. Johnson, Yong Chul Bae, Eun-Kyoung Kim
Abstract
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by a polyglutamine expansion in the androgen receptor (AR). Using gene expression analysis and ChIP sequencing, we mapped transcriptional changes in genetically engineered patient stem cell–derived motor neurons. We found that transcriptional dysregulation in SBMA can occur through AR-mediated histone modification. We detected reduced histone acetylation, along with decreased expression of genes encoding compensatory metabolic proteins and reduced substrate availability for mitochondrial function. Furthermore, we found that pyruvate supplementation corrected this deficiency and improved mitochondrial function and SBMA motor neuron viability. We propose that epigenetic dysregulation of metabolic genes contributes to reduced mitochondrial ATP production. Our results show a molecular link between altered epigenetic regulation and mitochondrial metabolism that contributes to neurodegeneration.
Authors
Naemeh Pourshafie, Ester Masati, Eric Bunker, Alec R. Nickolls, Parisorn Thepmankorn, Kory Johnson, Xia Feng, Tyler Ekins, Christopher Grunseich, Kenneth H. Fischbeck
Abstract
Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. SMN has key functions in multiple RNA pathways, including the biogenesis of small nuclear ribonucleoproteins (snRNPs) that are essential components of both major (U2-dependent) and minor (U12-dependent) spliceosomes. Here we investigated the specific contribution of U12 splicing dysfunction to SMA pathology through selective restoration of this RNA pathway in mouse models of varying phenotypic severity. We show that viral-mediated delivery of minor snRNA genes specifically improves select U12 splicing defects induced by SMN deficiency in cultured mammalian cells as well as in the spinal cord and dorsal root ganglia of SMA mice without increasing SMN expression. This approach resulted in a moderate amelioration of several parameters of the disease phenotype in SMA mice including survival, weight gain and motor function. Importantly, minor snRNA gene delivery improved aberrant splicing of the U12 intron-containing gene Stasimon and rescued the severe loss of proprioceptive sensory synapses on SMA motor neurons, which are early signatures of motor circuit dysfunction in mouse models. Taken together, these findings establish the direct contribution of U12 splicing dysfunction to synaptic deafferentation and motor circuit pathology in SMA.
Authors
Erkan Y. Osman, Meaghan Van Alstyne, Pei-Fen Yen, Francesco Lotti, Zhihua Feng, Karen K.Y. Ling, Chien-Ping Ko, Livio Pellizzoni, Christian L. Lorson
Abstract
Mitochondrial quality control is mediated by the PTEN-induced kinase 1 (PINK1), a cytoprotective protein that is dysregulated in inflammatory lung injury and neurodegenerative diseases. Here, we show that a ubiquitin E3 ligase receptor component, FBXO7, targets PINK1 for its cellular disposal. FBXO7, by mediating PINK1 ubiquitylation and degradation, was sufficient to induce mitochondrial injury and inflammation in experimental pneumonia. A computational simulation–based screen led to the identification of a small molecule, BC1464, which abrogated FBXO7 and PINK1 association, leading to increased cellular PINK1 concentrations and activities, and limiting mitochondrial damage. BC1464 exerted antiinflammatory activity in human tissue explants and murine lung inflammation models. Furthermore, BC1464 conferred neuroprotection in primary cortical neurons, human neuroblastoma cells, and patient-derived cells in several culture models of Parkinson’s disease. The data highlight a unique opportunity to use small molecule antagonists that disrupt PINK1 interaction with the ubiquitin apparatus to enhance mitochondrial quality, limit inflammatory injury, and maintain neuronal viability.
Authors
Yuan Liu, Travis B. Lear, Manish Verma, Kent Z.Q. Wang, P. Anthony Otero, Alison C. McKelvey, Sarah R. Dunn, Erin Steer, Nicholas W. Bateman, Christine Wu, Yu Jiang, Nathaniel M. Weathington, Mauricio Rojas, Charleen T. Chu, Bill B. Chen, Rama K. Mallampalli
Abstract
The impact of transient ischemic-hypoxemic insults on the developing fetal brain is poorly understood despite evidence suggesting an association with neurodevelopmental disorders such as schizophrenia and autism. To address this, we designed an aberrant uterine hypercontractility paradigm with oxytocin to better assess the consequences of acute, but transient, placental ischemia-hypoxemia in term pregnant rats. Using MRI, we confirmed that oxytocin-induced aberrant uterine hypercontractility substantially compromised uteroplacental perfusion. This was supported by the observation of oxidative stress and increased lactate concentration in the fetal brain. Genes related to oxidative stress pathways were significantly upregulated in male, but not female, offspring 1 hour after oxytocin-induced placental ischemia-hypoxemia. Persistent upregulation of select mitochondrial electron transport chain complex proteins in the anterior cingulate cortex of adolescent male offspring suggested that this sex-specific effect was enduring. Functionally, offspring exposed to oxytocin-induced uterine hypercontractility showed male-specific abnormalities in social behavior with associated region-specific changes in gene expression and functional cortical connectivity. Our findings, therefore, indicate that even transient but severe placental ischemia-hypoxemia could be detrimental to the developing brain and point to a possible mitochondrial link between intrauterine asphyxia and neurodevelopmental disorders.
Authors
Arvind Palanisamy, Tusar Giri, Jia Jiang, Annie Bice, James D. Quirk, Sara B. Conyers, Susan E. Maloney, Nandini Raghuraman, Adam Q. Bauer, Joel R. Garbow, David F. Wozniak
Abstract
Refractory neonatal seizures do not respond to first-line anti-seizure medications (ASMs) like phenobarbital (PB), a positive allosteric modulator for GABAA receptors. GABAA receptor-mediated inhibition is dependent upon electroneutral cation-chloride transporter KCC2 which mediates neuronal chloride extrusion and its age-dependent increase, postnatally shifts GABAergic signaling from depolarizing to hyperpolarizing. BDNF-TrkB activation following excitotoxic injury recruits downstream targets like PLCγ1, leading to KCC2 hypofunction. Here, the anti-seizure efficacy of TrkB agonists LM22A-4, HIOC, and Deoxygedunin (DG), on PB-refractory seizures, and post-ischemic TrkB-pathway activation was investigated in a mouse model (CD-1, P7) of refractory neonatal seizures. LM, a BDNF loop II mimetic, rescued PB-refractory seizures in a sexually dimorphic manner. Efficacy was associated with a significant reduction in the post-ischemic phosphorylation of TrkB at Y816, a site known to mediate post-ischemic KCC2 hypofunction via PLCγ1 activation. LM rescued ischemia-induced pKCC2-S940 dephosphorylation, preserving its membrane stability. Full TrkB agonists HIOC and DG similarly rescued PB-refractoriness. Chemogenetic inactivation of TrkB significantly reduced post-ischemic neonatal seizure burdens at P7. Sex differences identified in developmental expression profiles of TrkB and KCC2 may underlie the sexually dimorphic efficacy of LM. These results support a novel role for the TrkB receptor in the emergence of age-dependent refractory neonatal seizures.
Authors
Pavel A. Kipnis, Brennan J. Sullivan, Brandon M. Carter, Shilpa Kadam
Abstract
Imprinted genes are highly expressed in the hypothalamus; however, whether specific imprinted genes affect hypothalamic neuromodulators and their functions is unknown. It has been suggested that Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by lack of paternal expression at chromosome 15q11-q13, is characterized by hypothalamic insufficiency. Here, we investigate the role of the paternally expressed Snord116 gene within the context of sleep and metabolic abnormalities of PWS, and we report a significant role of this imprinted gene in the function and organization of the two main neuromodulatory systems of the lateral hypothalamus (LH), namely, the orexin (OX) and melanin concentrating hormone (MCH) systems. We observe that the dynamics between neuronal discharge in the LH and the sleep-wake states of mice with paternal deletion of Snord116 (PWScrm+/p–) are compromised. This abnormal state-dependent neuronal activity is paralleled by a significant reduction in OX neurons in the LH of mutants. Therefore, we propose that an imbalance between OX- and MCH-expressing neurons in the LH of mutants reflects a series of deficits manifested in the PWS, such as dysregulation of rapid eye movement (REM) sleep, food intake and temperature control.
Authors
Marta Pace, Matteo Falappa, Andrea Freschi, Edoardo Balzani, Chiara Berteotti, Viviana Lo Martire, Fatemeh Kaveh, Eivind Hovig, Giovanna Zoccoli, Roberto Amici, Matteo Cerri, Alfonso Urbanucci, Valter Tucci
The cellular basis of protease activated receptor type 2 (PAR2) evoked mechanical and affective pain
Abstract
Protease-activated receptor 2 (PAR2) has long been implicated in inflammatory and visceral pain, but the cellular basis of PAR2-evoked pain has not been delineated. While PAR2-evoked pain has been attributed to sensory neuron expression, RNA-sequencing experiments show ambiguous F2rl1 mRNA detection. Moreover, many pharmacological tools for PAR2 are nonspecific, acting also on the Mas-related GPCR family (Mrg) that are highly enriched in sensory neurons. We sought to bring clarity to the cellular basis of PAR2 pain. We developed a PAR2 conditional mutant mouse and specifically deleted PAR2 in all sensory neurons using the PirtCre mouse line. Our behavioral findings show that PAR2 agonist-evoked mechanical hyperalgesia and facial grimacing, but not thermal hyperalgesia, is dependent on PAR2 expression in sensory neurons that project to the hind paw in male and female mice. F2rl1 mRNA is expressed in a discrete population (~4%) of mostly small-diameter sensory neurons that co-express the Nppb and IL31ra genes. This cell population has been implicated in itch, but our work shows that PAR2 activation in these cells causes clear pain-related behaviors from the skin. Our findings show that a discreet population of DRG sensory neurons mediate PAR2-evoked pain.
Authors
Shayne N. Hassler, Moeno Kume, Juliet Mwirigi, Ayesha Ahmad, Stephanie Shiers, Andi Wangzhou, Pradipta Ray, Sergei N. Belugin, Dhananjay K. Naik, Michael D. Burton, Josef Vagner, Scott Boitano, Armen N. Akopian, Gregory Dussor, Theodore J. Price
Abstract
Discovery strategies commonly focus on the identification of chemical libraries or natural products, but the modulation of endogenous ligands offers a much better therapeutic strategy due to their low adverse potential. Recently, we have seen that hexadecanamide (Hex) is present in hippocampal nuclei of normal mice as an endogenous ligand of peroxisome proliferator-activated receptor alpha (PPARα). This study underlines the importance of Hex in inducing the expression of brain-derived neurotrophic factor (BDNF) from hippocampal neurons via PPARα. The level of Hex was less in the hippocampus of 5xFAD mice as compared to non-Tg mice. Oral administration of Hex increased the level of this molecule in the hippocampus to stimulate BDNF and its downstream plasticity-associated molecules, promote synaptic functions in the hippocampus and improve memory and learning in 5xFAD mice. However, oral Hex remained unable to stimulate hippocampal plasticity and improve cognitive behaviors in 5xFADPparα-null (5x with global PPARα-/-) and 5xFADPparα-ΔHippo (5x with hippocampus-specific PPARα-/-) mice, indicating an essential role of hippocampal PPARα in Hex-mediated improvement in hippocampal functions. This is the first demonstration of protection of hippocampal functions by oral administration of a hippocampus-based drug, suggesting that hexadecanamide may be explored for therapeutic intervention in AD.
Authors
Dhruv R. Patel, Avik Roy, Sumita Raha, Madhuchhanda Kundu, Frank Gonzalez, Kalipada Pahan
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