Journal
BIOLOGICAL PSYCHIATRY
Volume 83, Issue 5, Pages 438-446Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2017.06.007
Keywords
Aromatic amino acid decarboxylase; DOPA decarboxylase; Dopamine; Neurodegeneration; Serotonin; Tau
Categories
Funding
- Department of Veterans Affairs Merit Review Grant [1147891]
- Bright Focus Foundation [A2014438S]
- National Institutes of Health National Institute of General Medical Sciences Medical Genetics Postdoctoral Training Program [T32-GM-007454]
Ask authors/readers for more resources
BACKGROUND: The microtubule-associated protein tau accumulates into toxic aggregates in multiple neurodegenerative diseases. We found previously that loss of D-2-family dopamine receptors ameliorated tauopathy in multiple models including a Caenorhabditis elegans model of tauopathy. METHODS: To better understand how loss of D-2-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 D-2 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 D-2-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available