Prion protein inCaenorhabditis elegans

Abstract

The infectious agent of prion diseases is believed to be nucleic acid-free particles composed of misfolded conformational isomers of a host protein known as prion protein (PrP). Although this "protein-only" concept is generally accepted, decades of extensive research have not been able to elucidate the mechanisms by which PrP misfolding leads to neurodegeneration and infectivity. The challenges in studying prion diseases relate in part to the limitations of mammalian prion models, which include the long incubation period post-infection until symptoms develop, the high expense of maintaining mammals for extended periods, as well as safety issues. In order to develop prion models incorporating a genetically tractable simple system with a well-defined neuronal system, we generated transgenic C. elegans expressing the mouse PrP behind the pan-neuronal ric-19 promoter (P ric-19 ). We show here that high expression of P ric-19 ::PrP in C. elegans can result in altered morphology, defective mobility and shortened lifespan. Low expression of P ric-19 ::PrP, however, does not cause any detectable harm. Using the dopamine neuron specific promoter P dat-1 , we also show that expression of the murine BAX, a pro-apoptotic member of the Bcl-2 family, causes dopamine neuron destruction in the nematode. However, co-expression of PrP inhibits BAX-mediated dopamine neuron degeneration, demonstrating for the first time that PrP has anti-BAX activity in living animals. Thus, these distinct PrP-transgenic C. elegans lines recapitulate a number of functional and neuropathological features of mammalian prion models and provide an opportunity for facile identification of genetic and environmental contributors to prion-associated pathology.

Using C. elegans to discover therapeutic compounds for ageing-associated neurodegenerative diseases

“…G2019S causes more rapid progression of behavioural deficits than others GW5074, indoline; sorafenib [ 60 ] BY250 ; baEx129 [P dat - 1 ::LRRK2(G2019S/D1994A)] UA215, UA216 lin - 15(n765ts) X; Is [P dat - 1 ::LRRK2 (WT,R1441C, G2019S, K1347A) + P dat - 1 :GFP + lin - 15 ( + ) ] SGC722, SGC851, SGC856, SGC862 TTT-3002 and LRRK2-IN1 [ 61 , 129 ] lin - 15(n765ts) X; cwrEx900 [P dat -1::GFP, P dat -1:: LRRK2(R1441C/A2016T), lin - 15( + ) ] SG900, SGC910 Double mutants displayed DAergic defects and neurodegeneration similar to R1441C- and G2019S-LRRK2 models. [ 61 ] Prion lin - 15(n765ts); [P mec - 7 ::PrP(WT, PG13) + P Str - 1 : GFP; P mec - 7 ::GFP + lin - 15 ( + ) ] Mechanosensory neurons Progressive loss of response to touch at the tail caused by mutant (PG13-PrP) PrP expression without causing cell death Quinacrine, resveratrol [ 130 ] P ric - 19 ::PrP + P ric - 19 ::GFP cgIs51, cgIs52, cgIs53 Constitutive pan-neuronal High PrP levels cause abnormal morphology, striking neuropathogenic phenotypes and remarkable reductions in lifespan [ 131 ] rmIs319 [P unc - 54 ::sup35(rΔ2-5, nm, r2e2 )::yfp], AM801, AM803, AM806 …”

Using WormBase: A Genome Biology Resource for Caenorhabditis elegans and Related Nematodes

“…C. elegans has also been used to study obesity [41] and prion diseases (modeled in C. elegans via the transgenic expression of the prion protein) [42]. …”

“…A review of the C. elegans literature corpus indicates that the worm has been used as a genetic model system for several diseases; examples include neuromuscular diseases like Amyotrophic Lateral Sclerosis (ALS) and Duchenne Muscular Dystrophy [36], complex neurological diseases like Parkinson’s and Alzheimer’s [37], ciliary diseases like Polycystic kidney disease (PKD) and Bardet-Biedl syndrome [38,39] and premature aging syndromes like Werner syndrome [40]. C. elegans has also been used to study obesity [41] and prion diseases (modeled in C. elegans via the transgenic expression of the prion protein) [42].…”

Caenorhabditis elegans as a model system for studying aging-associated neurodegenerative diseases

“…Furthermore, animals expressing PG13-PrP in a src-2 (a C. elegans Fyn-related kinase ortholog) null background showed a significant reduction in neuronal dysfunction induced by mutant PrP, suggesting a role for Fyn-related kinase signaling in mediating prion neurotoxicity. Another PrP model relies on pan-neuronal expression of the endogenous mouse PrP [ 136 ]. Here, molecules of murine PrP were N-glycosylated, GPI-anchored, and found on neuronal plasma membranes, consistent with mammalian studies of PrP expression.…”