title: Telomere shortening leads to an acceleration of synucleinopathy and impaired microglia response in a genetic mouse model.
abstract: Parkinson's disease is one of the most common neurodegenerative disorders of the elderly and ageing hence described to be a major risk factor. Telomere shortening as a result of the inability to fully replicate the ends of linear chromosomes is one of the hallmarks of ageing. The role of telomere dysfunction in neurological diseases and the ageing brain is not clarified and there is an ongoing discussion whether telomere shortening is linked to Parkinson's disease. Here we studied a mouse model of Parkinson's disease (Thy-1 [A30P] α-synuclein transgenic mouse model) in the background of telomere shortening (Terc knockout mouse model). α-synuclein transgenic mice with short telomeres (αSYN(tg/tg) G3Terc(-/-)) developed an accelerated disease with significantly decreased survival. This accelerated phenotype of mice with short telomeres was characterized by a declined motor performance and an increased formation of α-synuclein aggregates. Immunohistochemical analysis and mRNA expression studies revealed that the disease end-stage brain stem microglia showed an impaired response in αSYN(tg/tg) G3Terc(-/-) microglia animals. These results provide the first experimental data that telomere shortening accelerates α-synuclein pathology that is linked to limited microglia function in the brainstem.
authors.affiliation: Department of Internal Medicine III, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Scheffold
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, The Netherlands.
authors.forename: Inge R
authors.initials: IR
authors.lastname: Holtman
authors.affiliation: Department for Psychiatry and Psychotherapy, Molecular Psychiatry, Freiburg University Hospital, Hauptstrasse 5, 79104, Freiburg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Dieni
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, The Netherlands.
authors.forename: Nieske
authors.initials: N
authors.lastname: Brouwer
authors.affiliation: Department of Internal Medicine I, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Sarah-Fee
authors.initials: SF
authors.lastname: Katz
authors.affiliation: Department of Internal Medicine III, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Billy Michael Chelliah
authors.initials: BM
authors.lastname: Jebaraj
authors.affiliation: Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Hengerer
authors.affiliation: Department of Internal Medicine I, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Lechel
authors.affiliation: Department of Internal Medicine III, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, The Netherlands.
authors.forename: Erik W G M
authors.initials: EW
authors.lastname: Boddeke
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, The Netherlands.
authors.forename: Bart J L
authors.initials: BJ
authors.lastname: Eggen
authors.affiliation: Leibniz Institute for Age Research, Beutenbergstr. 11, 07745, Jena, Germany.
authors.forename: Karl-Lenhard
authors.initials: KL
authors.lastname: Rudolph
authors.affiliation: Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, The Netherlands. knut.biber@uniklinik-freiburg.de.|Department for Psychiatry and Psychotherapy, Molecular Psychiatry, Freiburg University Hospital, Hauptstrasse 5, 79104, Freiburg, Germany. knut.biber@uniklinik-freiburg.de.
authors.forename: Knut
authors.initials: K
authors.lastname: Biber
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009043:Motor Activity / Q000502:physiology; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D004856:Postural Balance / Q000502:physiology; D066263:Protein Aggregation, Pathological / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D059506:Telomere Shortening / Q000502:physiology*; D013997:Time Factors; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: Microglia; Parkinson’s disease; Telomeres; α-synuclein