C. elegans as a model organism to investigate molecular pathways involved with Parkinson's disease

Abstract

Parkinson's disease (PD) is an age-related movement disorder resulting, in part, from selective loss of dopaminergic neurons. Both invertebrate and mammalian models have been developed to study the cellular mechanisms altered during disease progression; nevertheless there are limitations within each model. Mammalian models remain invaluable in studying PD, but are expensive and time consuming. Here, we review genetic and environmental factors associated with PD, and describe how the nematode roundworm, Caenorhabditis elegans, has been used as a model organism for studying various aspects of this neurodegenerative disease. Both genetic and chemical screens have been conducted in C. elegans to identify molecular pathways, proteins, and small molecules that can impact PD pathology. Lastly, we highlight future areas of investigation, in the context of emerging fields in biology, where the nematode can be exploited to provide mechanistic insights and potential strategies to accelerate the path toward possible therapeutic intervention for PD. Developmental Dynamics 239:1282-1295,

Human Disease Models inDrosophila melanogasterand the Role of the Fly in Therapeutic Drug Discovery

“…Live worms expressing GFP in dopaminergic neurons are easily scorable for severity of response to treatments including lesioning with 6-hydroxy-2-dipropylaminotetralin or overexpression of ␣-synuclein (Nass et al, 2002;Lakso et al, 2003). Both high-throughput genetic and low-throughput chemical screens have been employed to identify genetic modifiers and pharmacological treatments that block neurodegeneration, some of which have been validated for efficacy in mammalian systems (Nass et al, 2005;Marvanova and Nichols, 2007;Harrington et al, 2010).…”

Modeling human neurodegenerative diseases in transgenic systems

“…As such to establish C. elegans models of AD, investigators have introduced various forms of transgenic human A . In muscle cells, human A 42 has been expressed using an A sequence fused to an artiWcial signal sequence designed to allow the extracellular release (Lakso et al 2003;Settivari et al 2009;Kuwahara et al 2006;Harrington et al 2010;Settivari et al 2009)…”

Age- and manganese-dependent modulation of dopaminergic phenotypes in a C. elegans DJ-1 genetic model of Parkinson's disease

“…The C. elegans nervous system is comprised of 302 cells sharing remarkably high gene conservation with the human nervous system. In particular, the machinery of the DAergic system is conserved in worms, making them an ideal model for PD research 35, 39, 40 . The C. elegans lifecycle includes an egg stage, four larval stages (L1-L4), a reproductively active adult stage, as well as an alternative life-stage referred to as dauer.…”