RRC ID 51462
Author Tyson T, Senchuk M, Cooper JF, George S, Van Raamsdonk JM, Brundin P.
Title Novel animal model defines genetic contributions for neuron-to-neuron transfer of α-synuclein.
Journal Sci Rep
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.
Volume 7(1)
Pages 7506
Published 2017-8-8
DOI 10.1038/s41598-017-07383-6
PII 10.1038/s41598-017-07383-6
PMID 28790319
PMC PMC5548897
MeSH Adenosine Triphosphatases / antagonists & inhibitors Adenosine Triphosphatases / genetics Adenosine Triphosphatases / metabolism Aldehyde Oxidoreductases / antagonists & inhibitors Aldehyde Oxidoreductases / genetics Aldehyde Oxidoreductases / metabolism Animals Autophagy / drug effects Autophagy / genetics* Brain / drug effects Brain / metabolism Brain / pathology Caenorhabditis elegans / genetics* Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / antagonists & inhibitors Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Cell Communication Discoidin Domain Receptor 2 / genetics Discoidin Domain Receptor 2 / metabolism Disease Models, Animal* Endocytosis / drug effects Exocytosis / drug effects Gene Expression Regulation Genes, Reporter Green Fluorescent Proteins / genetics Green Fluorescent Proteins / metabolism Humans Neurons / drug effects Neurons / metabolism Neurons / pathology Parkinson Disease, Secondary / drug therapy Parkinson Disease, Secondary / genetics* Parkinson Disease, Secondary / metabolism Parkinson Disease, Secondary / pathology Protein Aggregates / drug effects Protein Serine-Threonine Kinases / antagonists & inhibitors Protein Serine-Threonine Kinases / genetics Protein Serine-Threonine Kinases / metabolism Protein Transport / drug effects RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Sirolimus / pharmacology Spectrometry, Fluorescence Tryptophan Hydroxylase / genetics Tryptophan Hydroxylase / metabolism Ubiquitin-Protein Ligases / antagonists & inhibitors Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism alpha-Synuclein / chemistry alpha-Synuclein / genetics alpha-Synuclein / metabolism*
IF 3.998
Times Cited 15
C.elegans tm5447