Parker JA et al. (2004) J Mol Neurosci "Genetic and pharmacological suppression of polyglutamine-dependent neuronal dysfunction in Caenorhabditis elegans."

Parker JA, Abderrahmane S, Neri C, Holbert S, Lambert E

[J Mol Neurosci, 2004]

The identification of disease genes for several neurodegenerative illnesses has allowed for the development of disease models in experimental organisms. We discuss our approach to studying Huntington's disease, the best characterized of the polyglutamine (polyQ) expansion disorders. We have developed a system in Caenorhabditis elegans to study the effects of (polyQ)-dependent neuronal dysfunction at the resolution of two neurons in screening for genetic and pharmacological suppression. Our data suggest that C. elegans might be instructive in searching for targets and active compounds against polyglutamine neuronal toxicity.

Schmeisser K et al. (2019) Front Cell Dev Biol "Pleiotropic Effects of mTOR and Autophagy During Development and Aging."

Parker JA, Schmeisser K

[Front Cell Dev Biol, 2019]

Autophagy as a ubiquitous catabolic process causes degradation of cytoplasmic components and is generally considered to have beneficial effects on health and lifespan. In contrast, inefficient autophagy has been linked with detrimental effects on the organism and various diseases, such as Parkinson's disease. Previous research, however, showed that this paradigm is far from being black and white. For instance, it has been reported that increased levels of autophagy during development can be harmful, but become advantageous in the aging cell or organism, causing enhanced healthspan and even longevity. The antagonistic pleiotropy hypothesis postulates that genes, which control various traits in an organism, can be fitness-promoting in early life, but subsequently trigger aging processes later. Autophagy is controlled by the mechanistic target of rapamycin (mTOR), a key player of nutrient sensing and signaling and classic example of a pleiotropic gene. mTOR acts upstream of transcription factors such as FOXO, NRF, and TFEB, controlling protein synthesis, degradation, and cellular growth, thereby regulating fertility as well as aging. Here, we review recent findings about the pleiotropic role of autophagy during development and aging, examine the upstream factors, and contemplate specific mechanisms leading to disease, especially neurodegeneration.

Therrien M et al. (2014) Front Genet "Worming forward: amyotrophic lateral sclerosis toxicity mechanisms and genetic interactions in Caenorhabditis elegans."

Parker JA, Therrien M

[Front Genet, 2014]

Neurodegenerative diseases share pathogenic mechanisms at the cellular level including protein misfolding, excitotoxicity and altered RNA homeostasis among others. Recent advances have shown that the genetic causes underlying these pathologies overlap, hinting at the existence of a genetic network for neurodegeneration. This is perhaps best illustrated by the recent discoveries of causative mutations for amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Once thought to be distinct entities, it is now recognized that these diseases exist along a genetic spectrum. With this wealth of discoveries comes the need to develop new genetic models of ALS and FTD to investigate not only pathogenic mechanisms linked to causative mutations, but to uncover potential genetic interactions that may point to new therapeutic targets. Given the conservation of many disease genes across evolution, Caenorhabditis elegans is an ideal system to investigate genetic interactions amongst these genes. Here we review the use of C. elegans to model ALS and investigate a putative genetic network for ALS/FTD that may extend to other neurological disorders.