6-OHDA-induced dopaminergic neurodegeneration in Caenorhabditis elegans is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33

TY - JOUR

T1 - 6-OHDA-induced dopaminergic neurodegeneration in Caenorhabditis elegans is promoted by the engulfment pathway and inhibited by the transthyretin-related protein TTR-33

AU - Offenburger, Sarah-Lena

AU - Ho, Xue Yan

AU - Tachie-Menson, Theresa

AU - Coakley, Sean

AU - Hilliard, Massimo A.

AU - Gartner, Anton

N1 - This work was funded by a Wellcome Trust Programme grant to AG (0909444/Z/09/Z, https://wellcome.ac.uk/funding) and a Parkinson’s UK grant (G0912, https://www.parkinsons.org.uk/research/research-grants), together with infrastructure funding from a Wellcome Trust Strategic award (097045/B/11/Z). We acknowledge the Dundee Imaging Facility, which is supported by the Wellcome Trust Technology Platform award (097945/B/11/Z) and the MRC Next Generation Optical Microscopy award (MR/K015869/1). SLO was supported by a PhD fellowship from the Molecular and Cellular Biology programme funded by the Wellcome Trust and by ISSF funding from the Wellcome Trust. This work was also supported by an National Health and Medical Research Council (NHMRC, https://www.nhmrc.gov.au/) Senior Research Fellowship 1111042, Project Grants 1129367, 1068871, and an Australian Research Council (ARC, http://www.arc.gov.au/) Discovery Project 160104359 to MAH; University of Queensland, International Postgraduate Award to XYH, and a NHRMC/ARC Dementia Fellowship 1108489 to SC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2018/1/18

Y1 - 2018/1/18

N2 - Oxidative stress is linked to many pathological conditions including the loss of dopaminergic neurons in Parkinson's disease. The vast majority of disease cases appear to be caused by a combination of genetic mutations and environmental factors. We screened for genes protecting Caenorhabditis elegans dopaminergic neurons from oxidative stress induced by the neurotoxin 6-hydroxydopamine (6-OHDA) and identified the transthyretin-related gene ttr-33. The only described C. elegans transthyretin-related protein to date, TTR-52, has been shown to mediate corpse engulfment as well as axon repair. We demonstrate that TTR-52 and TTR-33 have distinct roles. TTR-33 is likely produced in the posterior arcade cells in the head of C. elegans larvae and is predicted to be a secreted protein. TTR-33 protects C. elegans from oxidative stress induced by paraquat or H2O2 at an organismal level. The increased oxidative stress sensitivity of ttr-33 mutants is alleviated by mutations affecting the KGB-1 MAPK kinase pathway, whereas it is enhanced by mutation of the JNK-1 MAPK kinase. Finally, we provide genetic evidence that the C. elegans cell corpse engulfment pathway is required for the degeneration of dopaminergic neurons after exposure to 6-OHDA. In summary, we describe a new neuroprotective mechanism and demonstrate that TTR-33 normally functions to protect dopaminergic neurons from oxidative stress-induced degeneration, potentially by acting as a secreted sensor or scavenger of oxidative stress.

AB - Oxidative stress is linked to many pathological conditions including the loss of dopaminergic neurons in Parkinson's disease. The vast majority of disease cases appear to be caused by a combination of genetic mutations and environmental factors. We screened for genes protecting Caenorhabditis elegans dopaminergic neurons from oxidative stress induced by the neurotoxin 6-hydroxydopamine (6-OHDA) and identified the transthyretin-related gene ttr-33. The only described C. elegans transthyretin-related protein to date, TTR-52, has been shown to mediate corpse engulfment as well as axon repair. We demonstrate that TTR-52 and TTR-33 have distinct roles. TTR-33 is likely produced in the posterior arcade cells in the head of C. elegans larvae and is predicted to be a secreted protein. TTR-33 protects C. elegans from oxidative stress induced by paraquat or H2O2 at an organismal level. The increased oxidative stress sensitivity of ttr-33 mutants is alleviated by mutations affecting the KGB-1 MAPK kinase pathway, whereas it is enhanced by mutation of the JNK-1 MAPK kinase. Finally, we provide genetic evidence that the C. elegans cell corpse engulfment pathway is required for the degeneration of dopaminergic neurons after exposure to 6-OHDA. In summary, we describe a new neuroprotective mechanism and demonstrate that TTR-33 normally functions to protect dopaminergic neurons from oxidative stress-induced degeneration, potentially by acting as a secreted sensor or scavenger of oxidative stress.

UR - https://www.scopus.com/pages/publications/85041297867

U2 - 10.1371/journal.pgen.1007125

DO - 10.1371/journal.pgen.1007125

M3 - Article

C2 - 29346382

SN - 1553-7390

VL - 14

SP - 1

EP - 27

JO - PLoS Genetics

JF - PLoS Genetics

IS - 1

M1 - e1007125

ER -