title: Progranulin contributes to endogenous mechanisms of pain defense after nerve injury in mice.
abstract: Progranulin haploinsufficiency is associated with frontotemporal dementia in humans. Deficiency of progranulin led to exaggerated inflammation and premature aging in mice. The role of progranulin in adaptations to nerve injury and neuropathic pain are still unknown. Here we found that progranulin is up-regulated after injury of the sciatic nerve in the mouse ipsilateral dorsal root ganglia and spinal cord, most prominently in the microglia surrounding injured motor neurons. Progranulin knockdown by continuous intrathecal spinal delivery of small interfering RNA after sciatic nerve injury intensified neuropathic pain-like behaviour and delayed the recovery of motor functions. Compared to wild-type mice, progranulin-deficient mice developed more intense nociceptive hypersensitivity after nerve injury. The differences escalated with aging. Knockdown of progranulin reduced the survival of dissociated primary neurons and neurite outgrowth, whereas addition of recombinant progranulin rescued primary dorsal root ganglia neurons from cell death induced by nerve growth factor withdrawal. Thus, up-regulation of progranulin after neuronal injury may reduce neuropathic pain and help motor function recovery, at least in part, by promoting survival of injured neurons and supporting regrowth. A deficiency in this mechanism may increase the risk for injury-associated chronic pain.
authors.affiliation: Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany.
authors.forename: Hee-Young
authors.initials: HY
authors.lastname: Lim
authors.forename: Boris
authors.initials: B
authors.lastname: Albuquerque
authors.forename: Annett
authors.initials: A
authors.lastname: Häussler
authors.forename: Thekla
authors.initials: T
authors.lastname: Myrczek
authors.forename: Aihao
authors.initials: A
authors.lastname: Ding
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000378:metabolism / Q000503:physiopathology; D000077155:Granulins; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000503:physiopathology*; D000077153:Progranulins; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000293:injuries* / Q000503:physiopathology; D015854:Up-Regulation
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D034741:RNA, Small Interfering