title: Schwann cells contribute to neurodegeneration in transthyretin amyloidosis.
abstract: Familial amyloidotic polyneuropathy (FAP) is one of the transthyretin (TTR) amyloidoses characterized by extracellular amyloid deposits and peripheral nerve involvement. Recently, we found significant expression of the TTR gene in Schwann cells of the peripheral nervous system. We hypothesized that local expression of variant TTR in Schwann cells may contribute to neurodegeneration in FAP. Schwann cells derived from the dorsal root ganglia (DRG) of transgenic mice expressing variant human TTR in a mouse null background were cultured long term to obtain spontaneously immortalized cell lines. We established an immortalized Schwann cell line, TgS1, derived from the transgenic mice. TgS1 cells synthesized variant TTR and secreted it into the medium. As sensory neuropathy usually arises early in FAP, we examined the effect of the conditioned medium derived from TgS1 cells on neurite outgrowth from DRG sensory neurons. Conditioned medium derived from TgS1 cells inhibited neurite outgrowth from the sensory neurons. TTR deposition in the DRG of aged transgenic mice was investigated by immunohistochemistry. TTR aggregates were observed in the cytoplasm of Schwann cells and satellite cells. Proteasome inhibition induced TTR aggregates as aggresomes in TgS1 cells. In conclusion, local variant TTR gene expression in Schwann cells might trigger neurodegeneration in FAP. We established a spontaneously immortalized Schwann cell line derived from familial amyloidotic polyneuropathy transgenic mice. Conditioned medium from the cells contained variant transthyretin (TTR), and inhibited neurite outgrowth of neurons. TTR aggregates were observed in the Schwann cells and satellite cells of aged mice. Proteasome inhibition induced TTR aggregates as aggresomes in the cultured cells. These results support the hypothesis that Schwann cells contribute to neurodegeneration in familial amyloidotic polyneuropathy (FAP).
authors.affiliation: Department of Neurology, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Tatsufumi
authors.initials: T
authors.lastname: Murakami
authors.affiliation: Department of Sensory and Motor Systems (ALS/Neuropathy Project), Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Sango
authors.affiliation: Department of Sensory and Motor Systems (ALS/Neuropathy Project), Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Watabe
authors.affiliation: Department of Sensory and Motor Systems (ALS/Neuropathy Project), Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Niimi
authors.affiliation: Department of Sensory and Motor Systems (ALS/Neuropathy Project), Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Takaku
authors.affiliation: Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamamura
authors.affiliation: Department of Neurology, Kawasaki Medical School, Kurashiki, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Sunada
mesh_terms: D028227:Amyloid Neuropathies, Familial / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D011228:Prealbumin / Q000096:biosynthesis*; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D011228:Prealbumin
keywords: Schwann cell; amyloidosis; dorsal root ganglia; neurodegeneration; transthyretin