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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra
We investigate the role of genetic deficiencies in mitodynamic processes in promoting neurodegeneration caused by exposure to mitochondrial DNA (mtDNA)-damaging ultraviolet C radiation (UVC) radiation and by exposure to the model neurotoxicant 6-hydroxydopamine (6-OHDA)
Sci. 2019, 20, 3202 or fission would be sensitized to UVC damage-induced dopaminergic neurodegeneration compared to wild-type animals
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra. Mice lacking mitophagy-related Parkin in combination with a “mutator” form of proofreading-deficient polymerase gamma (responsible for replication of mitochondrial DNA, or mtDNA) undergo early loss of dopaminergic neurons in the substantia nigra [9]. Mutations in other genes involved in mitochondrial dynamics may interact with environmental exposures to initiate or drive mitochondrial toxicity, as we have recently reviewed [19], and contribute to PD initiation or progression. These processes include mitochondrial fusion—or the combination of two mitochondria to form a larger organelle—and mitochondrial fission, which is the segregation of one mitochondrion into two daughter mitochondria [19].
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