Transthyretin abnormalities in amyotrophic lateral sclerosis: High molecular weight species in cerebrospinal fluid and stromal deposits in choroid plexus.

Transthyretin (TTR) is a plasma and cerebrospinal fluid (CSF) protein involved in transporting thyroid hormone and retinol, with additional roles in the central nervous system (CNS). The tetrameric structure of TTR is essential for its functions and tetramer dissociation and aggregation into pathological amyloid fibrils is implicated in multiple diseases. Altered levels of TTR have previously been described in amyotrophic lateral sclerosis (ALS) in both CSF and CNS tissue. However, whether altered TTR levels in ALS reflect TTR pathology in CSF or in the choroid plexus (CP) cells that synthesize CNS TTR is unknown. Here, we comprehensively assayed native and aggregated TTR in ALS patient CSF and postmortem ALS CP. Using a nondenaturing native polyacrylamide gel electrophoresis-based assay, we identified high molecular weight TTR aggregates in the CSF of ALS patients. We also observed increased levels of TTR RNA and protein in ALS CP, as well as TTR granule deposits in CP stroma of ALS but not control cases. Taken together, our results reveal new forms of TTR dysfunction in ALS and uncover TTR-related morphological abnormalities in the CP in ALS patients.