title: Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy.
abstract: Peripheral or central nerve injury is a frequent cause of chronic pain and the mechanisms are not fully understood. Using newly generated transgenic mice we show that progranulin overexpression in sensory neurons attenuates neuropathic pain after sciatic nerve injury and accelerates nerve healing. A yeast-2-hybrid screen revealed putative interactions of progranulin with autophagy-related proteins, ATG12 and ATG4b. This was supported by colocalization and proteomic studies showing regulations of ATG13 and ATG4b and other members of the autophagy network, lysosomal proteins and proteins involved in endocytosis. The association of progranulin with the autophagic pathway was functionally confirmed in primary sensory neurons. Autophagy and survival were impaired in progranulin-deficient neurons and improved in progranulin overexpressing neurons. Nerve injury in vivo caused an accumulation of LC3b-EGFP positive bodies in neurons of the dorsal root ganglia and nerves suggesting an impairment of autophagic flux. Overexpression of progranulin in these neurons was associated with a reduction of the stress marker ATF3, fewer protein aggregates in the injured nerve and enhanced stump healing. At the behavioral level, further inhibition of the autophagic flux by hydroxychloroquine intensified cold and heat nociception after sciatic nerve injury and offset the pain protection provided by progranulin. We infer that progranulin may assist in removal of protein waste and thereby helps to resolve neuropathic pain after nerve injury.
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Altmann
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hardt
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Fischer
authors.affiliation: Functional Proteomics, SFB815 Core Unit, Goethe-University, Frankfurt, Germany.
authors.forename: Juliana
authors.initials: J
authors.lastname: Heidler
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Lim
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Häussler
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Albuquerque
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Béla
authors.initials: B
authors.lastname: Zimmer
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Möser
authors.affiliation: Institute of Biochemistry II, Goethe-University Hospital, Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Behrends
authors.affiliation: Ozgene Pty Ltd., Bentley DC, WA 6983, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Koentgen
authors.affiliation: Functional Proteomics, SFB815 Core Unit, Goethe-University, Frankfurt, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Wittig
authors.affiliation: Molecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Mirko H H
authors.initials: MHH
authors.lastname: Schmidt
authors.affiliation: Institute of Pathobiochemistry, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Albrecht M
authors.initials: AM
authors.lastname: Clement
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University, Frankfurt, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.affiliation: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany. Electronic address: tegeder@em.uni-frankfurt.de.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000473:pathology; D063990:Gene Ontology; D000077155:Granulins; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009437:Neuralgia / Q000473:pathology*; D010147:Pain Measurement; D000077153:Progranulins; D011984:Sensory Receptor Cells / Q000378:metabolism*
chemical_list: C000608442:ATG13 protein, mouse; D051700:Activating Transcription Factor 3; C491049:Aif1 protein, mouse; D051017:Apoptosis Regulatory Proteins; C103002:Atf3 protein, mouse; D000071183:Autophagy-Related Proteins; D039481:CD11b Antigen; D002135:Calcium-Binding Proteins; D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D052118:Lysosomal-Associated Membrane Protein 1; C480860:Map1lc3b protein, mouse; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D000077153:Progranulins; D049452:Green Fluorescent Proteins; C582881:Atg4b protein, mouse; D003546:Cysteine Endopeptidases
keywords: Autophagy; Dorsal root ganglia; Nerve injury; Pain; Progranulin; Sensory neuron