Familial amyloidotic polyneuropathy (FAP) is one of the transthyretin (TTR) amyloidoses characterized by extracellular amyloid deposits and peripheral nerve involvement. The pathogenesis of neuropathy, and the mechanisms of the TTR deposited in the peripheral nervous system are completely unknown. 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. We examined the effect of the conditioned medium (CM) derived from TgS1 cells on neurite outgrowth from DRG sensory neurons. The CM inhibited neurite outgrowth from DRG sensory neurons. TTR deposition in the DRG of aged transgenic mice was also investigated by immunohistochemistry, and it revealed TTR aggregates in the cytoplasm of Schwann cells and satellite cells. TTR aggregates were examined in TgS1 cells. Proteasome inhibition induced TTR aggregates as aggresomes in the cells.
The expression of variant TTR in DRG Schwann cells may exert a toxic effect on sensory neurons, resulting in neurodegeneration. Involvement of the protein quality control system in Schwann cells with age could trigger TTR deposition in the DRG of the peripheral nervous system.