Journal article
Cellular clearance of circulating transthyretin decreases cell-nonautonomous proteotoxicity in Caenorhabditis elegans
Proceedings of the National Academy of Sciences - PNAS, Vol.115(33), pp.E7710-E7719
08/14/2018
DOI: 10.1073/pnas.1801117115
PMCID: PMC6099907
PMID: 30061394
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
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
modulation of aggregation-prone degradation that directly affects postmitotic tissue degeneration observed in the proteinopathies.
Details
- Title: Subtitle
- Cellular clearance of circulating transthyretin decreases cell-nonautonomous proteotoxicity in Caenorhabditis elegans
- Creators
- Kayalvizhi Madhivanan - Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037Erin R Greiner - Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037Miguel Alves-Ferreira - Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, 4150-171 Porto, PortugalDavid Soriano-Castell - Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037Nirvan Rouzbeh - Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037Carlos A Aguirre - Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037Johan F Paulsson - Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037Justin Chapman - Misfolding Diagnostics, San Diego, CA 92121Xin JiangFelicia K Ooi - Department of Biology, Aging Mind and Brain Initiative, University of Iowa, Iowa City, IA 52242Carolina Lemos - Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, 4150-171 Porto, PortugalAndrew Dillin - Howard Hughes Medical Institute, University of California, Berkeley, CA 94720Veena Prahlad - Department of Biology, Aging Mind and Brain Initiative, University of Iowa, Iowa City, IA 52242Jeffery W Kelly - The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037Sandra E Encalada - Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.115(33), pp.E7710-E7719
- Publisher
- United States
- DOI
- 10.1073/pnas.1801117115
- PMID
- 30061394
- PMCID
- PMC6099907
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- R01 DK046335 / NIDDK NIH HHS R01 AG038664 / NIA NIH HHS R01 AG050653 / NIA NIH HHS R01 AG049483 / NIA NIH HHS Howard Hughes Medical Institute R37 DK046335 / NIDDK NIH HHS
- Language
- English
- Date published
- 08/14/2018
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9983991979102771
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