Abstract
A hallmark common to many age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), is that patients develop proteinaceous deposits in their central nervous system (CNS). The progressive spreading of these inclusions from initially affected sites to interconnected brain areas is reminiscent of the behavior of bona fide prions in transmissible spongiform encephalopathies (TSEs), hence the term prion-like proteins has been coined. Despite intensive research, the exact mechanisms that facilitate the spreading of protein aggregation between cells, and the associated loss of neurons, remain poorly understood. As population demographics in many countries continue to shift to higher life expectancy, the incidence of neurodegenerative diseases is also rising. This represents a major challenge for healthcare systems and patients’ families, since patients require extensive support over several years and there is still no therapy to cure or stop these diseases. The model organism Caenorhabditis elegans offers unique opportunities to accelerate research and drug development due to its genetic amenability, its transparency, and the high degree of conservation of molecular pathways. Here, we will review how recent studies that utilize this soil dwelling nematode have proceeded to investigate the propagation and intercellular transmission of prions and prion-like proteins and discuss their relevance by comparing their findings to observations in other model systems and patients.
Highlights
Prion-like spreading of the yeast prion domain of Sup35 (NM), α-Syn, and HTT Exon1-polyQ97 as well as the non-cell autonomous toxicity associated with transthyretin (TTR) amyloidoses have been modeled in C. elegans (Table 1)
The identification of potential cofactors involved in the prion-like amplification and intercellular transmission of amyloidogenic proteins is of high relevance as it may lead to new therapeutic approaches
This Hsp70 disaggregation machinery is able to dissociate recombinant amyloid fibers composed of α-Syn, Tau, or HTT Exon1-polyQ48 proteins as well as detergent-insoluble protein species extracted from various model systems in vitro [121,122,123], which has raised the question of whether this activity is cytoprotective by dissolving protein aggregates or whether, on the contrary, it contributes to amyloid amplification by generating smaller fragments similar to the role of Hsp104 in yeast prion propagation
Summary
Adding sonicated pre-formed fibers to native monomers seeds their conversion and incorporation into the β-sheet rich amyloid fiber and bypasses the initial lag phase of primary nucleation This autocatalytic, templated self-assembly, facilitated by the ordered arrangement of the individual units in the amyloid fibril, is the molecular basis for prion-like propagation. Transmissibility, i.e., dissemination between cells or individuals, has long been considered an exclusive feature of PrPSc. the observation that naïve grafted neurons developed Lewy bodies, intercellular inclusions containing α-Syn [17], in subjects with PD was the first evidence that pathological α-Syn might act and can spread from affected to healthy neurons [18,19]. The induction of inclusion formation by local injection of synthetically generated seeds or extracted patient brain material in transgenic mice, expressing a disease related mutant form of the respective human protein, has been shown for all of the above-mentioned prion-like proteins [20,21,22,23,24]
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