Similar Patterns of Mitochondrial Vulnerability and Rescue Induced by Genetic Modification of α-Synuclein, Parkin, and DJ-1 in Caenorhabditis elegans

Abstract

How genetic and environmental factors interact in Parkinson disease is poorly understood. We have now compared the patterns of vulnerability and rescue of Caenorhabditis elegans with genetic modifications of three different genetic factors implicated in Parkinson disease (PD). We observed that expressing ␣-synuclein, deleting parkin (K08E3.7), or knocking down DJ-1 (B0432.2) or parkin produces similar patterns of pharmacological vulnerability and rescue. C. elegans lines with these genetic changes were more vulnerable than nontransgenic nematodes to mitochondrial complex I inhibitors, including rotenone, fenperoximate, pyridaben, or stigmatellin. In contrast, the genetic manipulations did not increase sensitivity to paraquat, sodium azide, divalent metal ions (Fe(II) or Cu(II)), or etoposide compared with the nontransgenic nematodes. Each of the PD-related lines was also partially rescued by the antioxidant probucol, the mitochondrial complex II activator, D-␤-hydroxybutyrate, or the anti-apoptotic bile acid tauroursodeoxycholic acid. Complete protection in all lines was achieved by combining D-␤-hydroxybutyrate with tauroursodeoxycholic acid but not with probucol. These results show that diverse PD-related genetic modifications disrupt the mitochondrial function in C. elegans, and they raise the possibility that mitochondrial disruption is a pathway shared in common by many types of familial PD.The etiology of Parkinson disease has both genetic and environmental components (1). Epidemiological studies show that PD 3 is more common in rural areas, and increased rates of PD are associated with the use of agricultural toxins, such as pesticides and herbicides (2). Attention has focused on inhibitors of the mitochondrial electron transport chain because some of the agricultural toxins implicated in PD are complex I inhibitors (2). In addition, ingestion of complex I inhibitors causes syndromes related to PD. The complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively kills dopaminergic neurons in many types of animals (1). Rotenone, another complex I inhibitor, also causes a PD-related syndrome in rats and causes multiple changes in the mitochondria of cultured neurons relevant to PD (3-6). These factors implicate disruption of mitochondrial function, and particularly complex I inhibition, in the etiology of PD.Many of the genes associated with familial cases of PD have been identified, but no clear consensus exists over whether the different disease-related proteins converge onto a common pathway. Mutation of ␣-synuclein (at A53T, A30P, or K46E) or duplication of ␣-synuclein is associated with familial parkinsonisms (7-10). Loss of the putative ubiquitin ligase, parkin, causes autosomal recessive juvenile parkinsonism (11). Mutations in the genes coding for UCH-L1, DJ-1, and PINK1 are also all associated with autosomal recessive PD, and mutations in LRRK2 are associated with autosomal dominant PD (12-15). ␣-Synuclein is a small ubiquitous protein that binds lipids and might regulate ves...

Paraquat and Parkinson's disease

“…MPP þ , rotenone and PQ have all been shown to alter Parkin solubility, which facilitates its aggregation, decreases proteasome activity and causes cell injury and death. 53 In contrast, in the C. elegans controlled genetic background, the sensitivity model proposed by Ved et al 44 has shown that PQ toxicity is not enhanced by the Parkinson-linked genetic modifications, at variance with chemicals exerting an effect specifically on mitochondrial complex I.…”

“…39 A major difference in the interaction with cellular proteins between PQ and complex I acting chemicals is also highlighted in a study carried out in C. elegans, in which the patterns of vulnerability and rescue have been compared after genetic manipulation. 44 Ved et al 44 created a susceptibility model in C. elegans by overexpressing a-synuclein (which is normally not expressed in the worm) and deleting Parkin or knocking down DJ-1. C. elegans lines with these transgenic traits were more vulnerable than non-transgenic worms to mitochondrial complex I inhibitors including Rotenone.…”

Parkin Protects against Mitochondrial Toxins and β-Amyloid Accumulation in Skeletal Muscle Cells

“…The link between parkin function and mitochondrial performance was further strengthened by data from an unbiased proteomic approach that showed alterations in mitochondrial function in the ventral midbrain of parkin-null mice and revealed systemic changes due to oxidative stress (15). Recent data using Caenorhabditis elegans devoid of parkin have reinforced the importance of this protein to mitochondrial function (16).…”

Parkinson's Disease Brain Mitochondrial Complex I Has Oxidatively Damaged Subunits and Is Functionally Impaired and Misassembled

“…Rare familial forms of parkinsonism transmitted in autosomal dominant or recessive patterns have been traced to mutations in multiple genes. For some of these autosomal forms of parkinsonism, mitochondrial dysfunction is emerging as a common theme of pathogenesis (Ved et al, 2005).…”