Publications by authors named "Britt A Berning"

6 Publications

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Polysialic acid in the rat brainstem and thoracolumbar spinal cord: Distribution, cellular location, and comparison with mouse.

J Comp Neurol 2021 03 4;529(4):811-827. Epub 2020 Aug 4.

Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.

Polysialic acid (polySia), a homopolymer of α2,8-linked glycans, is a posttranslational modification on a few glycoproteins, most commonly in the brain, on the neural cell adhesion molecule. Most research in the adult central nervous system has focused on its expression in higher brain regions, where its distribution coincides with regions known to exhibit high levels of synaptic plasticity. In contrast, scant attention has been paid to the expression of polySia in the hindbrain. The main aims of the study were to examine the distribution of polySia immunoreactivity in the brainstem and thoracolumbar spinal cord, to compare the distribution of polySia revealed by two commercial antibodies commonly used for its investigation, and to compare labeling in the rat and mouse. We present a comprehensive atlas of polySia immunoreactivity: we report that polySia labeling is particularly dense in the dorsal tegmentum, medial vestibular nuclei and lateral parabrachial nucleus, and in brainstem regions associated with autonomic function, including the dorsal vagal complex, A5, rostral ventral medulla, A1, and midline raphe, as well as sympathetic preganglionic neurons in the spinal cord and central targets of primary sensory afferents (nucleus of the solitary tract, spinal trigeminal nucleus, and dorsal horn [DH]). Ultrastructural examination showed labeling was present predominantly on the plasma membrane/within the extracellular space/in or on astrocytes. Labeling throughout the brainstem and spinal cord were very similar for the two antibodies and was eliminated by the polySia-specific sialidase, Endo-NF. Similar patterns of distribution were found in rat and mouse brainstem with differences evident in DH.
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http://dx.doi.org/10.1002/cne.24982DOI Listing
March 2021

Genetic and immunopathological analysis of CHCHD10 in Australian amyotrophic lateral sclerosis and frontotemporal dementia and transgenic TDP-43 mice.

J Neurol Neurosurg Psychiatry 2020 02 5;91(2):162-171. Epub 2019 Nov 5.

Macquarie University Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia.

Objective: Since the first report of gene mutations in amyotrophiclateral sclerosis (ALS)/frontotemporaldementia (FTD) patients, genetic variation in has been inconsistently linked to disease. A pathological assessment of the CHCHD10 protein in patient neuronal tissue also remains to be reported. We sought to characterise the genetic and pathological contribution of CHCHD10 to ALS/FTD in Australia.

Methods: Whole-exome and whole-genome sequencing data from 81 familial and 635 sporadic ALS, and 108 sporadic FTD cases, were assessed for genetic variation in . CHCHD10 protein expression was characterised by immunohistochemistry, immunofluorescence and western blotting in control, ALS and/or FTD postmortem tissues and further in a transgenic mouse model of TAR DNA-binding protein 43 (TDP-43) pathology.

Results: No causal, novel or disease-associated variants in were identified in Australian ALS and/or FTD patients. In human brain and spinal cord tissues, CHCHD10 was specifically expressed in neurons. A significant decrease in CHCHD10 protein level was observed in ALS patient spinal cord and FTD patient frontal cortex. In a TDP-43 mouse model with a regulatable nuclear localisation signal (rNLS TDP-43 mouse), CHCHD10 protein levels were unaltered at disease onset and early in disease, but were significantly decreased in cortex in mid-stage disease.

Conclusions: Genetic variation in is not a common cause of ALS/FTD in Australia. However, we showed that in humans, CHCHD10 may play a neuron-specific role and a loss of CHCHD10 function may be linked to ALS and/or FTD. Our data from the rNLS TDP-43 transgenic mice suggest that a decrease in CHCHD10 levels is a late event in aberrant TDP-43-induced ALS/FTD pathogenesis.
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http://dx.doi.org/10.1136/jnnp-2019-321790DOI Listing
February 2020

The Pathobiology of TDP-43 C-Terminal Fragments in ALS and FTLD.

Front Neurosci 2019 11;13:335. Epub 2019 Apr 11.

Neurodegeneration Pathobiology Laboratory, Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.

During neurodegenerative disease, the multifunctional RNA-binding protein TDP-43 undergoes a vast array of post-translational modifications, including phosphorylation, acetylation, and cleavage. Many of these alterations may directly contribute to the pathogenesis of TDP-43 proteinopathies, which include most forms of amyotrophic lateral sclerosis (ALS) and approximately half of all frontotemporal dementia, pathologically identified as frontotemporal lobar degeneration (FTLD) with TDP-43 pathology. However, the relative contributions of the various TDP-43 post-translational modifications to disease remain unclear, and indeed some may be secondary epiphenomena rather than disease-causative. It is therefore critical to determine the involvement of each modification in disease processes to allow the design of targeted treatments. In particular, TDP-43 C-terminal fragments (CTFs) accumulate in the brains of people with ALS and FTLD and are therefore described as a neuropathological signature of these diseases. Remarkably, these TDP-43 CTFs are rarely observed in the spinal cord, even in ALS which involves dramatic degeneration of spinal motor neurons. Therefore, TDP-43 CTFs are not produced non-specifically in the course of all forms of TDP-43-related neurodegeneration, but rather variably arise due to additional factors influenced by regional heterogeneity in the central nervous system. In this review, we summarize how TDP-43 CTFs are generated and degraded by cells, and critique evidence from studies of TDP-43 CTF pathology in human disease tissues, as well as cell and animal models, to analyze the pathophysiological relevance of TDP-43 CTFs to ALS and FTLD. Numerous studies now indicate that, although TDP-43 CTFs are prevalent in ALS and FTLD brains, disease-related pathology is only variably reproduced in TDP-43 CTF cell culture models. Furthermore, TDP-43 CTF expression in both transgenic and viral-mediated models largely fails to induce motor or behavioral dysfunction reminiscent of human disease. We therefore conclude that although TDP-43 CTFs are a hallmark of TDP-43-related neurodegeneration in the brain, they are not a primary cause of ALS or FTLD.
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http://dx.doi.org/10.3389/fnins.2019.00335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470282PMC
April 2019

Polysialic Acid Regulates Sympathetic Outflow by Facilitating Information Transfer within the Nucleus of the Solitary Tract.

J Neurosci 2017 07 2;37(27):6558-6574. Epub 2017 Jun 2.

Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, 2109 New South Wales, Australia,

Expression of the large extracellular glycan, polysialic acid (polySia), is restricted in the adult, to brain regions exhibiting high levels of plasticity or remodeling, including the hippocampus, prefrontal cortex, and the nucleus of the solitary tract (NTS). The NTS, located in the dorsal brainstem, receives constant viscerosensory afferent traffic as well as input from central regions controlling sympathetic nerve activity, respiration, gastrointestinal functions, hormonal release, and behavior. Our aims were to determine the ultrastructural location of polySia in the NTS and the functional effects of enzymatic removal of polySia, both and polySia immunoreactivity was found throughout the adult rat NTS. Electron microscopy demonstrated polySia at sites that influence neurotransmission: the extracellular space, fine astrocytic processes, and neuronal terminals. Removing polySia from the NTS had functional consequences. Whole-cell electrophysiological recordings revealed altered intrinsic membrane properties, enhancing voltage-gated K currents and increasing intracellular Ca Viscerosensory afferent processing was also disrupted, dampening low-frequency excitatory input and potentiating high-frequency sustained currents at second-order neurons. Removal of polySia in the NTS of anesthetized rats increased sympathetic nerve activity, whereas functionally related enzymes that do not alter polySia expression had little effect. These data indicate that polySia is required for the normal transmission of information through the NTS and that changes in its expression alter sympathetic outflow. polySia is abundant in multiple but discrete brain regions, including sensory nuclei, in both the adult rat and human, where it may regulate neuronal function by mechanisms identified here. All cells are coated in glycans (sugars) existing predominantly as glycolipids, proteoglycans, or glycoproteins formed by the most complex form of posttranslational modification, glycosylation. How these glycans influence brain function is only now beginning to be elucidated. The adult nucleus of the solitary tract has abundant polysialic acid (polySia) and is a major site of integration, receiving viscerosensory information which controls critical homeostatic functions. Our data reveal that polySia is a determinant of neuronal behavior and excitatory transmission in the nucleus of the solitary tract, regulating sympathetic nerve activity. polySia is abundantly expressed at distinct brain sites in adult, including major sensory nuclei, suggesting that sensory transmission may also be influenced via mechanisms described here. These findings hint at the importance of elucidating how other glycans influence neural function.
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http://dx.doi.org/10.1523/JNEUROSCI.0200-17.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596603PMC
July 2017

The role of pancreatic polypeptide in the regulation of energy homeostasis.

Mol Cell Endocrinol 2015 Dec 27;418 Pt 1:33-41. Epub 2015 Jun 27.

Neurological Diseases Division, Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia; School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address:

Imbalances in normal regulation of food intake can cause obesity and related disorders. Inadequate therapies for such disorders necessitate better understanding of mechanisms that regulate energy homeostasis. Pancreatic polypeptide (PP), a robust anorexigenic hormone, effectively modulates food intake and energy homeostasis, thus potentially aiding anti-obesity therapeutics. Intra-gastric and intra-intestinal infusion of nutrients stimulate PP secretion from the gastrointestinal tract, leading to vagal stimulation that mediates complex actions via the neuropeptide Y4 receptor in arcuate nucleus of the hypothalamus, subsequently activating key hypothalamic nuclei and dorsal vagal complex of the brainstem to influence energy homeostasis and body composition. Novel studies indicate affinity of PP for the relatively underexplored neuropeptide y6 receptor, mediating actions via the suprachiasmatic nucleus and pathways involving vasoactive intestinal polypeptide and insulin like growth factor 1. This review highlights detailed mechanisms by which PP mediates its actions on energy balance through various areas in the brain.
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http://dx.doi.org/10.1016/j.mce.2015.06.028DOI Listing
December 2015

Pancreatic polypeptide controls energy homeostasis via Npy6r signaling in the suprachiasmatic nucleus in mice.

Cell Metab 2014 Jan;19(1):58-72

Neuroscience Program, Garvan Institute of Medical Research, St. Vincent's Hospital, 384 Victoria Street, Darlinghurst, Sydney NSW 2010, Australia; UNSW Medicine, ASGM Building, University of NSW, Botany Street, Sydney 2052, Australia. Electronic address:

Y-receptors control energy homeostasis, but the role of Npy6 receptors (Npy6r) is largely unknown. Young Npy6r-deficient (Npy6r(-/-)) mice have reduced body weight, lean mass, and adiposity, while older and high-fat-fed Npy6r(-/-) mice have low lean mass with increased adiposity. Npy6r(-/-) mice showed reduced hypothalamic growth hormone releasing hormone (Ghrh) expression and serum insulin-like growth factor-1 (IGF-1) levels relative to WT. This is likely due to impaired vasoactive intestinal peptide (VIP) signaling in the suprachiasmatic nucleus (SCN), where we found Npy6r coexpressed in VIP neurons. Peripheral administration of pancreatic polypeptide (PP) increased Fos expression in the SCN, increased energy expenditure, and reduced food intake in WT, but not Npy6r(-/-), mice. Moreover, intraperitoneal (i.p.) PP injection increased hypothalamic Ghrh mRNA expression and serum IGF-1 levels in WT, but not Npy6r(-/-), mice, an effect blocked by intracerebroventricular (i.c.v.) Vasoactive Intestinal Peptide (VPAC) receptors antagonism. Thus, PP-initiated signaling through Npy6r in VIP neurons regulates the growth hormone axis and body composition.
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http://dx.doi.org/10.1016/j.cmet.2013.11.019DOI Listing
January 2014
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