Cell-to-cell Transmission of Polyglutamine Aggregates inC. elegans

Abstract

Huntington disease (HD) is an inherited neurodegenerative disorder characterized by motor and cognitive dysfunction caused by expansion of polyglutamine (polyQ) repeat in exon 1 of huntingtin (HTT). In patients, the number of glutamine residues in polyQ tracts are over 35, and it is correlated with age of onset, severity, and disease progression. Expansion of polyQ increases the propensity for HTT protein aggregation, process known to be implicated in neurodegeneration. These pathological aggregates can be transmitted from neuron to another neuron, and this process may explain the pathological spreading of polyQ aggregates. Here, we developed an in vivo model for studying transmission of polyQ aggregates in a highly quantitative manner in real time. HTT exon 1 with expanded polyQ was fused with either N-terminal or C-terminal fragments of Venus fluorescence protein and expressed in pharyngeal muscles and associated neurons, respectively, of C. elegans. Transmission of polyQ proteins was detected using bimolecular fluorescence complementation (BiFC). Mutant polyQ (Q97) was transmitted much more efficiently than wild type polyQ (Q25) and forms numerous inclusion bodies as well. The transmission of Q97 was gradually increased with aging of animal. The animals with polyQ transmission exhibited degenerative phenotypes, such as nerve degeneration, impaired pharyngeal pumping behavior, and reduced life span. The C. elegans model presented here would be a useful in vivo model system for the study of polyQ aggregate propagation and might be applied to the screening of genetic and chemical modifiers of the propagation.

Shedding a new light on Huntington’s disease: how blood can both propagate and ameliorate disease pathology

“…The seeding capacity of mHTT has now been shown along with neuronal toxicity in several cell models [22,25] as well as in in vivo paradigms (i.e. mouse, drosophila and C. elegans) [9,24,[26][27][28] and a number of putative mechanisms of spread have been postulated, including trans-synaptic and paracrine transmission, as well as exocytosis. Although compelling evidence has been provided for some of these mechanisms in HD, none of these studies have evaluated transmission from sources outside of the CNS.…”

C. elegans Models to Study the Propagation of Prions and Prion-Like Proteins

“…These studies tracked the transmission of the prion-like protein under investigation either by direct observation of fluorescence signal in tissues that do not express the transgene [ 58 , 59 , 60 , 61 ] or by the use of bimolecular fluorescence complementation (BiFC) ( Figure 1 ). For the latter case, α-Syn or HTT Exon1-polyQ97 tagged with one non-fluorescent half of a fluorescent protein (enhanced GFP (EGFP) or Venus) were expressed in a subset of neurons and the same proteins tagged with the non-fluorescent complementary other half expressed in the neighboring pharynx [ 62 , 63 , 64 ] or in an interconnected neuronal population [ 65 ]. The appearance of fluorescence signal in the neurons and the pharynx could be attributed to the transmission and subsequent complementation of the fluorescent protein fragments attached to the respective prion-like proteins.…”

Dynamics of Ischemia-Dependence as Neurodegeneration

“…The simple formulated increment of molecular aggregation is a highly permissive accumulation that includes also defining terms of aggregation as wellprojected in terms of misfolded or unfolded molecules such as alpha synuclein or polyglutamine traits. Expansion of polyglutamine increases the propensity for Huntingtin protein aggregation, a process known to be implicated in neurodegeneration [25].…”