Mutations in PARKIN( PDR-1 ) increases Reproductive Fitness in C. elegans

1. Mutations in PARKIN(PDR-1) increases Reproductive Fitness in C. elegans  1,2Tracy Barhydt,2Suzanne Angeli, David Killilea, 2Pankaj Kapahi, 2Gordon Lithgow,2Julie Andersen 1Dominican University of California, 50 Acacia Ave., San Rafael, California 2Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, California INTRODUCTION Parkinson’s disease (PD) is largely an idiopathic disease that includes contributions from both genetic and environmental factors, with aging itself being the largest risk factor.,Although most cases of PD are idiopathic, rare genetic forms of the disease do exist. In these cases, an important unanswered question is why mutations that cause the disease have come to be maintained within the human population? One possibility is based on what is known as the Antagonist Pleiotropic Theory (APT) of Aging, a theory that states that genes that confer reproductive benefit early in life may result in detrimental effects with post-reproductive aging2 We have made a series of observations in the model organism Caenorhabditiselegans that worms carrying a mutation the homozygous gene, pdr-1, display increased reproductive fitness. This suggests that familial PARKIN mutation may have a beneficial effect in terms of natural selection even though its known clinical effect in PD patients bearing this mutation is detrimental. This data provides the first clues as to why this particular PD-related mutation may be maintained within the population. we have asked whether increased fitness may be due to enhanced mitochondrial function during reproduction. Additionally, we contemplate if the environmental factor manganese (Mn), which has been identified as a risk factor for the disease, alters reproductive fitness in relation to this gene mutation. METHODS AND RESULTS RESULTS continued.. INTRODUCT Endogenous Mn Level in Larvae worms by ICP-AES pdr-1(lg103) shows increased Membrane Potential (MMP) * A B * * Figure 1. Broodsize is the number of total progeny in the worm, usually over a five day period. * (lg103) Figure 3. Two different experiments to determine putative mechanism of increased reproductive fitness in pdr-1(lg103). A) Analyzed large population of dried worms by Inductively-Coupled Plasma (ICP). One biological replicate. B) Detreming mitochondria membrane potential by exposing worms to Tetramethylrhodaminemethy ester (TMRM ) for 24 hours. P<0.05 PUTATIVE MECHANISMS What is the Mechanism for increased Reproductive Fitness? How did we test Darwinian Fitness ? PATHOLOGY: Selective loss of Dopamine neurons in the substanianigra pars compacta (SNc) in the midbrain. Yalemedicalgroup.com Figure 2. Both wild-type and pdr-1(lg103) competed for food sources under multiple generations. To determine allele frequency of worms at generation, genotype was determined by PCR. Medialweekly.wordpress.com SUMMARY • A single gene mutation demonstrates a putative example of Antagonistic Pleiotropy Theory • pdr-1(lg103) confers reproductive fitness • Mn metabolism may be the mechanism • pdr-1(lg103) has increased mitochondrial membrane potential which may provide answers to suggested enhanced mitochondrial function to increase early reproductive fitness Caenorhabditiselegansas a Parkinson’s Disease Model Excellent for: References • Harrington, Adam, Shusei Hamamichi, Guy A. Caldwell and Kim Caldwell C. elegansas a Model Organism to Investigate Molecular Pathways Involved with Parkinson’s Disease, Developmental Dynamics 239 (2010) 2. Williams, G. C. Pleiotropy, Natural Selection, and the Evolution of Senescence. Evolution 11, 398-411 (1957). Aging Studies Environmental toxin exposure Genetic tool C. elegansLifecycle Wormbase.com