TY - JOUR A1 - Plum, Sarah A1 - Eggers, Britta A1 - Helling, Stefan A1 - Stepath, Markus A1 - Theiss, Carsten A1 - Leite, Renata E. P. A1 - Molina, Mariana A1 - Grinberg, Lea T. A1 - Riederer, Peter A1 - Gerlach, Manfred A1 - May, Caroline A1 - Marcus, Katrin T1 - Proteomic characterization of synaptosomes from human substantia nigra indicates altered mitochondrial translation in Parkinson's disease JF - Cells N2 - The pathological hallmark of Parkinson's disease (PD) is the loss of neuromelanin-containing dopaminergic neurons within the substantia nigra pars compacta (SNpc). Additionally, numerous studies indicate an altered synaptic function during disease progression. To gain new insights into the molecular processes underlying the alteration of synaptic function in PD, a proteomic study was performed. Therefore, synaptosomes were isolated by density gradient centrifugation from SNpc tissue of individuals at advanced PD stages (N = 5) as well as control subjects free of pathology (N = 5) followed by mass spectrometry-based analysis. In total, 362 proteins were identified and assigned to the synaptosomal core proteome. This core proteome comprised all proteins expressed within the synapses without regard to data analysis software, gender, age, or disease. The differential analysis between control subjects and PD cases revealed that CD9 antigen was overrepresented and fourteen proteins, among them Thymidine kinase 2 (TK2), mitochondrial, 39S ribosomal protein L37, neurolysin, and Methionine-tRNA ligase (MARS2) were underrepresented in PD suggesting an alteration in mitochondrial translation within synaptosomes. KW - synaptosomes KW - proteomics KW - Parkinson's disease KW - substantia nigra pars compacta KW - mitochondrial pathology KW - mitochondrial translation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219978 SN - 2073-4409 VL - 9 IS - 12 ER - TY - JOUR A1 - Weselek, Grit A1 - Keiner, Silke A1 - Fauser, Mareike A1 - Wagenführ, Lisa A1 - Müller, Julia A1 - Kaltschmidt, Barbara A1 - Brandt, Moritz D. A1 - Gerlach, Manfred A1 - Redecker, Christoph A1 - Hermann, Andreas A1 - Storch, Alexander T1 - Norepinephrine is a negative regulator of the adult periventricular neural stem cell niche JF - Stem Cells N2 - The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell‐extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ‐olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4‐fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus‐related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease. KW - adult neurogenesis KW - hippocampus KW - noradrenaline KW - norepinephrine KW - olfactory bulb neurogenesis KW - subventricular zone Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218250 VL - 38 IS - 9 SP - 1188 EP - 1201 ER - TY - JOUR A1 - Fauser, Mareike A1 - Weselek, Grit A1 - Hauptmann, Christine A1 - Markert, Franz A1 - Gerlach, Manfred A1 - Hermann, Andreas A1 - Storch, Alexander T1 - Catecholaminergic Innervation of Periventricular Neurogenic Regions of the Developing Mouse Brain JF - Frontiers in Neuroanatomy N2 - The major catecholamines—dopamine (DA) and norepinephrine (NE)—are not only involved in synaptic communication but also act as important trophic factors and might ultimately be involved in mammalian brain development. The catecholaminergic innervation of neurogenic regions of the developing brain and its putative relationship to neurogenesis is thus of pivotal interest. We here determined DA and NE innervation around the ventricular/subventricular zone (VZ/SVZ) bordering the whole ventricular system of the developing mouse brain from embryonic day 14.5 (E14.5), E16.5, and E19.5 until postnatal day zero (P0) by histological evaluation and HPLC with electrochemical detection. We correlated these data with the proliferation capacity of the respective regions by quantification of MCM\(^{2+}\) cells. During development, VZ/SVZ catecholamine levels dramatically increased between E16.5 and P0 with DA levels increasing in forebrain VZ/SVZ bordering the lateral ventricles and NE levels raising in midbrain/hindbrain VZ/SVZ bordering the third ventricle, the aqueduct, and the fourth ventricle. Conversely, proliferating MCM\(^{2+}\) cell counts dropped between E16.5 and E19.5 with a special focus on all VZ/SVZs outside the lateral ventricles. We detected an inverse strong negative correlation of the proliferation capacity in the periventricular neurogenic regions (log-transformed MCM\(^{2+}\) cell counts) with their NE levels (r = −0.932; p < 0.001), but not their DA levels (r = 0.440; p = 0.051) suggesting putative inhibitory effects of NE on cell proliferation within the periventricular regions during mouse brain development. Our data provide the first framework for further demandable studies on the functional importance of catecholamines, particularly NE, in regulating neural stem/progenitor cell proliferation and differentiation during mammalian brain development. KW - brain development KW - ventricular zone KW - catecholamines KW - norepinephrine KW - dopamine KW - neurogenesis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212485 VL - 14 ER -