title: Loss of MyD88 alters neuroinflammatory response and attenuates early Purkinje cell loss in a spinocerebellar ataxia type 6 mouse model.
abstract: Spinocerebellar ataxia type 6 (SCA6) is dominantly inherited neurodegenerative disease, caused by an expansion of CAG repeat encoding a polyglutamine (PolyQ) tract in the Cav2.1 voltage-gated calcium channel. Its key pathological features include selective degeneration of the cerebellar Purkinje cells (PCs), a common target for PolyQ-induced toxicity in various SCAs. Mutant Cav2.1 confers toxicity primarily through a toxic gain-of-function mechanism; however, its molecular basis remains elusive. Here, we studied the cerebellar gene expression patterns of young Sca6-MPI(118Q/118Q) knockin (KI) mice, which expressed mutant Cav2.1 from an endogenous locus and recapitulated many phenotypic features of human SCA6. Transcriptional signatures in the MPI(118Q/118Q) mice were distinct from those in the Sca1(154Q/2Q) mice, a faithful SCA1 KI mouse model. Temporal expression profiles of the candidate genes revealed that the up-regulation of genes associated with microglial activation was initiated before PC degeneration and was augmented as the disease progressed. Histological analysis of the MPI(118Q/118Q) cerebellum showed the predominance of M1-like pro-inflammatory microglia and it was concomitant with elevated expression levels of tumor necrosis factor, interleukin-6, Toll-like receptor (TLR) 2 and 7. Genetic ablation of MyD88, a major adaptor protein conveying TLR signaling, altered expression patterns of M1/M2 microglial phenotypic markers in the MPI(118Q/118Q) cerebellum. More importantly, it ameliorated PC loss and partially rescued motor impairments in the early disease phase. These results suggest that early neuroinflammatory response may play an important role in the pathogenesis of SCA6 and its modulation could pave the way for slowing the disease progression during the early stage of the disease.
authors.affiliation: Center for Brain Integration Research, Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology (JST), Tokyo 102-8666, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Aikawa
authors.affiliation: Department of Bioinformatics, Medical Research Institute, Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology (JST), Tokyo 102-8666, Japan, Center for Genomic and Regenerative Medicine, Juntendo University, Tokyo 113-0033, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.affiliation: Department of Bioinformatics, Medical Research Institute, Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology (JST), Tokyo 102-8666, Japan, Department of Social Services and Healthcare Management, International University of Health and Welfare, Tochigi 324-8501, Japan and.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Iijima-Tsutsui
authors.affiliation: Department of Neurology and Neurogical Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan, Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology (JST), Tokyo 102-8666, Japan.
authors.forename: Kinya
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Center for Brain Integration Research.
authors.forename: Miyano
authors.initials: M
authors.lastname: Sakurai
authors.affiliation: Department of Bioinformatics, Medical Research Institute, Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology (JST), Tokyo 102-8666, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Center for Brain Integration Research, Department of Neurology and Neurogical Science, Tokyo Medical and Dental University, Tokyo 113-8510, Japan, Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology (JST), Tokyo 102-8666, Japan, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
authors.affiliation: Center for Brain Integration Research, Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology (JST), Tokyo 102-8666, Japan, keinuro@tmd.ac.jp.
authors.forename: Kei
authors.initials: K
authors.lastname: Watase
mesh_terms: D000818:Animals; D015415:Biomarkers; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism; D009043:Motor Activity; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics*; D011689:Purkinje Cells / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger