title: Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement.
abstract: Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1-/-)] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra-/-)] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra-/-mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1-/-mice. Casp1-/-mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra-/-mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1-/-mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.
authors.affiliation: Department of Clinical and Experimental Medicine, Division of Cell Biology, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Andrea
authors.initials: A
authors.lastname: Stojakovic
authors.affiliation: The Arcos-Burgos Group, Genome Science Department, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Paz-Filho
authors.affiliation: The Arcos-Burgos Group, Genome Science Department, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Arcos-Burgos
authors.affiliation: Mind and Brain Theme, South Australian Health and Medical Research Institute and Flinders, University of South Australia, Adelaide, Australia.
authors.forename: Julio
authors.initials: J
authors.lastname: Licinio
authors.affiliation: Mind and Brain Theme, South Australian Health and Medical Research Institute and Flinders, University of South Australia, Adelaide, Australia. mali.wong@sahmri.com.
authors.forename: Ma-Li
authors.initials: ML
authors.lastname: Wong
authors.affiliation: The Arcos-Burgos Group, Genome Science Department, John Curtin School of Medical Research, Australian National University, Canberra, Australia. Claudio.mastronardi@anu.edu.au.|Mind and Brain Theme, South Australian Health and Medical Research Institute and Flinders, University of South Australia, Adelaide, Australia. Claudio.mastronardi@anu.edu.au.
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Mastronardi
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D002452:Cell Count; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity; D009068:Movement; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D045442:Rotarod Performance Test; D015398:Signal Transduction; D013378:Substantia Nigra / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D014446:Tyrosine 3-Monooxygenase
keywords: Dopaminergic neuron; Microglia; Open-field; Rotarod; Substantia nigra