Abstract
Cell-to-cell spreading of misfolded α-synuclein (α-syn) is suggested to contribute to the progression of neuropathology in Parkinson's disease (PD). Compelling evidence supports the hypothesis that misfolded α-syn transmits from neuron-to-neuron and seeds aggregation of the protein in the recipient cells. Furthermore, α-syn frequently appears to propagate in the brains of PD patients following a stereotypic pattern consistent with progressive spreading along anatomical pathways. We have generated a C. elegans model that mirrors this progression and allows us to monitor α-syn neuron-to-neuron transmission in a live animal over its lifespan. We found that modulation of autophagy or exo/endocytosis, affects α-syn transfer. Furthermore, we demonstrate that silencing C. elegans orthologs of PD-related genes also increases the accumulation of α-syn. This novel worm model is ideal for screening molecules and genes to identify those that modulate prion-like spreading of α-syn in order to target novel strategies for disease modification in PD and other synucleinopathies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphatases / antagonists & inhibitors
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Adenosine Triphosphatases / genetics
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Adenosine Triphosphatases / metabolism
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Aldehyde Oxidoreductases / antagonists & inhibitors
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Aldehyde Oxidoreductases / genetics
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Aldehyde Oxidoreductases / metabolism
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Animals
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Autophagy / drug effects
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Autophagy / genetics*
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Brain / drug effects
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Brain / metabolism
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Brain / pathology
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Caenorhabditis elegans / genetics*
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Caenorhabditis elegans / metabolism
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Caenorhabditis elegans Proteins / antagonists & inhibitors
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism
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Cell Communication
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Discoidin Domain Receptor 2 / genetics
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Discoidin Domain Receptor 2 / metabolism
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Disease Models, Animal*
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Endocytosis / drug effects
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Exocytosis / drug effects
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Gene Expression Regulation
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Genes, Reporter
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Humans
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Neurons / drug effects
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Neurons / metabolism
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Neurons / pathology
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Parkinson Disease, Secondary / drug therapy
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Parkinson Disease, Secondary / genetics*
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Parkinson Disease, Secondary / metabolism
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Parkinson Disease, Secondary / pathology
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Protein Aggregates / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Transport / drug effects
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Sirolimus / pharmacology
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Spectrometry, Fluorescence
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Tryptophan Hydroxylase / genetics
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Tryptophan Hydroxylase / metabolism
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Ubiquitin-Protein Ligases / antagonists & inhibitors
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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alpha-Synuclein / chemistry
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alpha-Synuclein / genetics
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alpha-Synuclein / metabolism*
Substances
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Caenorhabditis elegans Proteins
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Protein Aggregates
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RNA, Small Interfering
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alpha-Synuclein
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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Tryptophan Hydroxylase
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Aldehyde Oxidoreductases
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DJR-1.2 protein, C elegans
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Ubiquitin-Protein Ligases
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parkin protein
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Discoidin Domain Receptor 2
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LRK-1 protein, C elegans
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Protein Serine-Threonine Kinases
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Adenosine Triphosphatases
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CATP-6 protein, C elegans
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Sirolimus