RRC ID |
51462
|
著者 |
Tyson T, Senchuk M, Cooper JF, George S, Van Raamsdonk JM, Brundin P.
|
タイトル |
Novel animal model defines genetic contributions for neuron-to-neuron transfer of α-synuclein.
|
ジャーナル |
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.
|
巻・号 |
7(1)
|
ページ |
7506
|
公開日 |
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
|
引用数 |
15
|
リソース情報 |
線虫 |
tm5447 |