title: Transient IKK2 activation in astrocytes initiates selective non-cell-autonomous neurodegeneration.
abstract: Neuroinflammation is associated with a wide range of neurodegenerative disorders, however the specific contribution to individual disease pathogenesis and selective neuronal cell death is not well understood. Inflammatory cerebellar ataxias are neurodegenerative diseases occurring in various autoimmune/inflammatory conditions, e.g. paraneoplastic syndromes. However, how inflammatory insults can cause selective cerebellar neurodegeneration in the context of these diseases remains open, and appropriate animal models are lacking. A key regulator of neuroinflammatory processes is the NF-κB signalling pathway, which is activated by the IκB kinase 2 (IKK2) in response to various pathological conditions. Importantly, its activation is sufficient to initiate neuroinflammation on its own.
  
  
  
  To investigate the contribution of IKK/NF-κB-mediated neuroinflammation to neurodegeneration, we established conditional mouse models of cerebellar neuroinflammation, which depend either on the tetracycline-regulated expression of IKK2 in astrocytes or Cre-recombination based IKK2 activation in Bergmann glia.
  
  
  
  We demonstrate that IKK2 activation for a limited time interval in astrocytes is sufficient to induce neuroinflammation, astrogliosis and loss of Purkinje neurons, resembling the pathogenesis of inflammatory cerebellar ataxias. We identified IKK2-driven irreversible dysfunction of Bergmann glia as critical pathogenic event resulting in Purkinje cell loss. This was independent of Lipocalin 2, an acute phase protein secreted by reactive astrocytes and well known to mediate neurotoxicity. Instead, downregulation of the glutamate transporters EAAT1 and EAAT2 and ultrastructural alterations suggest an excitotoxic mechanism of Purkinje cell degeneration.
  
  
  
  Our results suggest a novel pathogenic mechanism how diverse inflammatory insults can cause inflammation/autoimmune-associated cerebellar ataxias. Disease-mediated elevation of danger signals like TLR ligands and inflammatory cytokines in the cerebellum activates IKK2/NF-κB signalling in astrocytes, which as a consequence triggers astrogliosis-like activation of Bergmann glia and subsequent non-cell-autonomous Purkinje cell degeneration. Notably, the identified hit and run mechanism indicates only an early window for therapeutic interventions.
authors.affiliation: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.|Neural Stem Cell Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Lattke
authors.affiliation: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Reichel
authors.affiliation: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Magnutzki
authors.affiliation: Core Facility Small Animal MRI, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Alireza
authors.initials: A
authors.lastname: Abaei
authors.affiliation: Core Facility Small Animal MRI, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Rasche
authors.affiliation: Central Facility for Electron Microscopy, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Walther
authors.affiliation: Immunity and Cancer Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
authors.forename: Dinis P
authors.initials: DP
authors.lastname: Calado
authors.affiliation: CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Ferger
authors.affiliation: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany. thomas.wirth@uni-ulm.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.affiliation: Institute of Physiological Chemistry, Ulm University, Albert-Einstein-Allee 11, 89081, Ulm, Germany. bernd.baumann@uni-ulm.de.
authors.forename: Bernd
authors.initials: B
authors.lastname: Baumann
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism*; D004195:Disease Models, Animal; D005911:Gliosis / Q000473:pathology; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse
keywords: Bergmann glia; Cerebellar ataxia; EAAT; Excitotoxicity; Glutamate transporter; IKK; NF-kappaB; Neuroinflammation; Purkinje cell degeneration