Cellular clearance of circulating transthyretin decreases cell-nonautonomous proteotoxicity in Caenorhabditis elegans

Proc Natl Acad Sci U S A. 2018 Aug 14;115(33):E7710-E7719. doi: 10.1073/pnas.1801117115. Epub 2018 Jul 30.

Abstract

Cell-autonomous and cell-nonautonomous mechanisms of neurodegeneration appear to occur in the proteinopathies, including Alzheimer's and Parkinson's diseases. However, how neuronal toxicity is generated from misfolding-prone proteins secreted by nonneuronal tissues and whether modulating protein aggregate levels at distal locales affects the degeneration of postmitotic neurons remains unknown. We generated and characterized animal models of the transthyretin (TTR) amyloidoses that faithfully recapitulate cell-nonautonomous neuronal proteotoxicity by expressing human TTR in the Caenorhabditis elegans muscle. We identified sensory neurons with affected morphological and behavioral nociception-sensing impairments. Nonnative TTR oligomer load and neurotoxicity increased following inhibition of TTR degradation in distal macrophage-like nonaffected cells. Moreover, reducing TTR levels by RNAi or by kinetically stabilizing natively folded TTR pharmacologically decreased TTR aggregate load and attenuated neuronal dysfunction. These findings reveal a critical role for in trans modulation of aggregation-prone degradation that directly affects postmitotic tissue degeneration observed in the proteinopathies.

Keywords: aggregation; cell-nonautonomous; neurodegeneration; nonnative oligomers; polyneuropathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Neuropathies / genetics
  • Amyloid Neuropathies / metabolism
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans / cytology
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Humans
  • Prealbumin / genetics
  • Prealbumin / metabolism*
  • Protein Aggregates*
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism

Substances

  • Caenorhabditis elegans Proteins
  • Prealbumin
  • Protein Aggregates