Gene-by-environment interactions are thought to underlie the majority of idiopathic cases of neurodegenerative disease. Recently, we reported that an environmental metabolite extracted from
Streptomyces venezuelae increases ROS and damages mitochondria, leading to eventual neurodegeneration of
C. elegans dopaminergic neurons. Here we link those data to idiopathic disease models that predict loss of protein handling as a component of disorder progression. We demonstrate that the bacterial metabolite leads to proteostatic disruption in multiple protein-misfolding models and has the potential to synergistically enhance the toxicity of aggregate-prone proteins. Genetically, this metabolite is epistatically regulated by loss-of-function to
pink-1, the
C. elegans PARK6 homolog responsible for mitochondrial maintenance and autophagy in other animal systems. In addition, the metabolite works through a genetic pathway analogous to loss-of-function in the ubiquitin proteasome system (UPS), which we find is also epistatically regulated by loss of PINK-1 homeostasis. To determine remitting counter agents, we investigated several established antioxidants and found that glutathione (GSH) can significantly protect against metabolite-induced proteostasis disruption. In addition, GSH protects against the toxicity of MG132 and can compensate for the combined loss of both
pink-1 and the E3 ligase
pdr-1, a Parkin homolog. In assessing the impact of this metabolite on mitochondrial maintenance, we observe that it causes fragmentation of mitochondria that is attenuated by GSH and an initial surge in PINK-1-dependent autophagy. These studies mechanistically advance our understanding of a putative environmental contributor to neurodegeneration and factors influencing
in vivo neurotoxicity.Protein homeostasis (proteostasis) encompasses the process of translation, folding, compartmentalization, and degradation of proteins to maintain the long-term survival and functionality of the cell.
1, 2, 3 When proteins become misfolded they must be refolded or degraded to prevent disruptions to critical processes that result from proteotoxic stress.
3, 4 Surveillance machinery that combats proteotoxic stress includes the ubiquitin proteasome system (UPS), retrograde chaperone-inducing signaling systems termed unfolded protein responses (UPR), and bulk destruction through autophagy. The cell also utilizes protein clearance machinery to induce the destruction of entire organelles, such as mitochondria, when they no longer function correctly
5, 6 to protect the cell from reactive oxygen species (ROS). The last line of defense includes antioxidants in order to maintain a reduced intracellular state and attenuate damage to proteins.
7, 8, 9, 10, 11 Often, these regulated mechanisms are challenged by both the environment and genetic susceptibility factors. The integration of both, via gene-by-environment interactions, has been hypothesized to underlie many idiopathic neurodegenerative disorders.
12, 13, 14 Understanding how the environment contributes to disease pathologies is important for understanding neurodegeneration.Sources of environmental stressors are understudied and largely limited to human-derived toxicants such as pesticides like rotenone.
14, 15 However, people living in agricultural environs are often at a greater risk of developing neurodegenerative disorders that cannot be accounted for by human-derived toxicants alone.
16 Environmental contributors may come from natural sources like metabolite-producing bacteria. For instance, bacterial sources have been reported to induce DOPA-responsive movement disorders in mice.
17 Mechanistically, competition strategies among bacteria that produce antibiotics and small metabolites like phenazines that limit the growth of other bacterial species may have off-target effects on mitochondrial homeostasis, leading to ROS, protein damage, and neurodegeneration.
18 Indeed, proteostatic dysfunction, altered mitochondrial dynamics, and elevated ROS production are characteristics of sporadic Parkinson''s disease (PD).
19, 20, 21Our laboratory previously demonstrated neurodegeneration induced by unreported small compounds within the growth media of the Gram-positive soil bacterium
Streptomyces venezuelae.
22, 23, 24 These bacterial products induce neuronal death in both
C. elegans and cultured human neurons,
22 disrupt mitochondrial complex I, induce ROS, and decrease ATP production.
25 However, how these observations link to protein homeostasis has not been explored. Here we report that the active fraction of the
S. venezuelae media induces disruptions in protein homeostasis, glutathione (GSH)-tractable
α-synuclein toxicity, that UPS disruptions are epistatically regulated by loss-of-function to the PARK9 homolog
pink-1, and that PINK1-dependent autophagy results in mitochondrial morphology disruptions. These observations indicate that
pink-1 and UPS functionality are required for metabolite-induced protein toxicity in
C. elegans, suggesting that these pathways may be linked and that environmental contributors to neurodegenerative disease may proceed through pathways implicated in familial forms.
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