Found in Translation: The Utility of C. elegans Alpha-Synuclein Models of Parkinson's Disease

Abstract

Parkinson's Disease (PD) is the second-most common neurodegenerative disease in the world, yet the fundamental and underlying causes of the disease are largely unknown, and treatments remain sparse and impotent. Several biological systems have been employed to model the disease but the nematode roundworm Caenorhabditis elegans (C. elegans) shows unique promise among these to disinter the elusive factors that may prevent, halt, and/or reverse PD phenotypes. Some of the most salient of these C. elegans models of PD are those that position the misfolding-prone protein alpha-synuclein (α-syn), a hallmark pathological component of PD, as the primary target for scientific interrogation. By transgenic expression of human α-syn in different tissues, including dopamine neurons and muscle cells, the primary cellular phenotypes of PD in humans have been recapitulated in these C. elegans models and have already uncovered multifarious genetic factors and chemical compounds that attenuate dopaminergic neurodegeneration. This review describes the paramount discoveries obtained through the application of different α-syn models of PD in C. elegans and highlights their established utility and respective promise to successfully uncover new conserved genetic modifiers, functional mechanisms, therapeutic targets and molecular leads for PD with the potential to translate to humans.

Keywords: C. elegans; Parkinson; alpha-synuclein; dopamine; neurodegeneration.

Figure 1

The process of α-syn oligomerization and fibrilization. Monomers of α-syn are small, soluble and have the capacity to associate together and oligomerize. These soluble oligomers are thought to be cytotoxic and act as the major contributor to neurodegeneration and neuronal deficits. Over time, oligomers have the potential to fold into β-sheet-containing fibrils, which constitute Lewy Bodies in PD.

Figure 2

A progressive, age-dependent C. elegans α-syn model of PD [18]. (A) A worm expressing solely Green Fluorescent Protein (GFP) in the 8 DA neurons, with GFP being driven under the dopamine neuron-specific dat-1 promoter for visualization. Arrows with long tails indicate the 4 CEP neuron processes, arrowheads indicate the 2 ADE neuron processes and arrows with short tails indicate the 2 PDE neuron processes. (B) A worm expressing both GFP and human, wild-type α-syn in the DA neurons being driven under the dopamine neuron-specific dat-1 promoter, allowing visualization of the 6 DA neurons located in the head region. Arrows indicate non-degenerated CEP neuron processes and arrowheads indicate non-degenerated ADE neuron processes. (C) A worm expressing both GFP and human, wild-type α-syn in the DA neurons being driven under the dat-1 promoter, allowing visualization of the 6 DA neurons located in the head region. Red arrows indicate degenerated CEP neuron processes and the red arrowhead represents a degenerated ADE neuron process. (D) A representation of the neuroanatomy of the 6 DA neurons in the head region of C. elegans. Ventral and dorsal CEP neurons are shown, along with the ADE neurons.

Figure 3

A summary of some of the putative factors and processes that can be investigated using C. elegans α-syn models of PD.

Figure 4

Use of C. elegans to model human α-syn misfolding. (A) A closeup image of a muscle cell in a transgenic worm expressing human, wild-type α-syn translationally fused to Green Fluorescent Protein (GFP) driven under the body wall muscle cell-specific unc-54 promoter. Arrowheads indicate areas of large accumulations of misfolded α-syn. (B) A closeup of a worm muscle cell co-expressing human, wild-type α-syn translationally fused to GFP and the chaperone protein, TOR-2, driven as distinct expression constructs by the body wall muscle cell-specific unc-54 promoter. TOR-2 serves to attenuate the amount of α-syn misfolding; the resulting GFP expression appears soluble and without puncta, indicating minimal misfolding/accumulation. (C) A closeup of a worm muscle cell expressing human, wild-type α-syn translationally fused to GFP in the presence of the chaperone protein TOR-2, both driven under the unc-54 promoter. In this panel, a gene has been knocked down via RNAi that enhances α-syn misfolding. Arrows indicate areas of visible α-syn::GFP.