RRC ID 51414
著者 Kow RL, Sikkema C, Wheeler JM, Wilkinson CW, Kraemer BC.
タイトル DOPA Decarboxylase Modulates Tau Toxicity.
ジャーナル Biol Psychiatry
Abstract BACKGROUND:The microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. We found previously that loss of D2-family dopamine receptors ameliorated tauopathy in multiple models including a Caenorhabditis elegans model of tauopathy.
METHODS:To better understand how loss of D2-family dopamine receptors can ameliorate tau toxicity, we screened a collection of C. elegans mutations in dopamine-related genes (n = 45) for changes in tau transgene-induced behavioral defects. These included many genes responsible for dopamine synthesis, metabolism, and signaling downstream of the D2 receptors.
RESULTS:We identified one dopamine synthesis gene, DOPA decarboxylase (DDC), as a suppressor of tau toxicity in tau transgenic worms. Loss of the C. elegans DDC gene, bas-1, ameliorated the behavioral deficits of tau transgenic worms, reduced phosphorylated and detergent-insoluble tau accumulation, and reduced tau-mediated neuron loss. Loss of function in other genes in the dopamine and serotonin synthesis pathways did not alter tau-induced toxicity; however, their function is required for the suppression of tau toxicity by bas-1. Additional loss of D2-family dopamine receptors did not synergize with bas-1 suppression of tauopathy phenotypes.
CONCLUSIONS:Loss of the DDC bas-1 reduced tau-induced toxicity in a C. elegans model of tauopathy, while loss of no other dopamine or serotonin synthesis genes tested had this effect. Because loss of activity upstream of DDC could reduce suppression of tau by DDC, this suggests the possibility that loss of DDC suppresses tau via the combined accumulation of dopamine precursor levodopa and serotonin precursor 5-hydroxytryptophan.
巻・号 83(5)
ページ 438-446
公開日 2018-3-1
DOI 10.1016/j.biopsych.2017.06.007
PII S0006-3223(17)31667-0
PMID 28751068
PMC PMC5732084
MeSH Animals Animals, Genetically Modified Behavior, Animal / physiology Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Disease Models, Animal Dopa Decarboxylase / genetics Dopa Decarboxylase / metabolism* Dopamine / metabolism* Serotonin / metabolism* Tauopathies / metabolism* tau Proteins / metabolism* tau Proteins / toxicity
IF 11.984
引用数 3
リソース情報
線虫 tm351