RRC ID 59504
Author Hartman JH, Gonzalez-Hunt C, Hall SM, Ryde IT, Caldwell KA, Caldwell GA, Meyer JN.
Title Genetic Defects in Mitochondrial Dynamics in Caenorhabditis elegans Impact Ultraviolet C Radiation- and 6-hydroxydopamine-Induced Neurodegeneration.
Journal Int J Mol Sci
Abstract BACKGROUND:Parkinson's disease (PD) is one of the most common neurodegenerative disorders involving devastating loss of dopaminergic neurons in the substantia nigra. Early steps in PD pathogenesis include mitochondrial dysfunction, and mutations in mitochondrial genes have been linked to familial forms of the disease. However, low penetrance of mutations indicates a likely important role for environmental factors in PD risk through gene by environment interactions. Herein, we study how genetic deficiencies in mitochondrial dynamics processes including fission, fusion, and mitophagy interact with environmental exposures to impact neurodegeneration.
METHODS:We utilized the powerful model organism Caenorhabditis elegans to study ultraviolet C radiation (UVC)- and 6-hydroxydopamine-induced degeneration of fluorescently-tagged dopaminergic neurons in the background of fusion deficiency (MFN1/2 homolog, fzo-1), fission deficiency (DMN1L homolog, drp-1), and mitochondria-specific autophagy (mitophagy) deficiency (PINK1 and PRKN homologs, pink-1 and pdr-1).
RESULTS:Overall, we found that deficiency in either mitochondrial fusion or fission sensitizes nematodes to UVC exposure (used to model common environmental pollutants) but protects from 6-hydroxydopamine-induced neurodegeneration. By contrast, mitophagy deficiency makes animals more sensitive to these stressors with an interesting exception-pink-1 deficiency conferred remarkable protection from 6-hydroxydopamine. We found that this protection could not be explained by compensatory antioxidant gene expression in pink-1 mutants or by differences in mitochondrial morphology.
CONCLUSIONS:Together, our results support a strong role for gene by environment interactions in driving dopaminergic neurodegeneration and suggest that genetic deficiency in mitochondrial processes can have complex effects on neurodegeneration.
Volume 20(13)
Published 2019-6-29
DOI 10.3390/ijms20133202
PII ijms20133202
PMID 31261893
PMC PMC6651461
MeSH Animals Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics Dopaminergic Neurons / drug effects Dopaminergic Neurons / metabolism* Dopaminergic Neurons / radiation effects Dynamins / genetics GTP Phosphohydrolases / genetics Mitochondrial Dynamics* Mitophagy Oxidopamine / toxicity Parkinson Disease / etiology Parkinson Disease / genetics* Protein Serine-Threonine Kinases / genetics Radiation Tolerance / genetics* Ubiquitin-Protein Ligases / genetics Ultraviolet Rays / adverse effects
IF 4.183
Times Cited 5
C.elegans tm1779 tm598 tm1133 tm1108